Analyte monitoring device and methods of use

ABSTRACT

An analyte monitor includes a sensor, a sensor control unit, and a display unit. The sensor has, for example, a substrate, a recessed channel formed in the substrate, and conductive material disposed in the recessed channel to form a working electrode. The sensor control unit typically has a housing adapted for placement on skin and is adapted to receive a portion of an electrochemical sensor. The sensor control unit also includes two or more conductive contacts disposed on the housing and configured for coupling to two or more contact pads on the sensor. A transmitter is disposed in the housing and coupled to the plurality of conductive contacts for transmitting data obtained using the sensor. The display unit has a receiver for receiving data transmitted by the transmitter of the sensor control unit and a display coupled to the receiver for displaying an indication of a level of an analyte. The analyte monitor may also be part of a drug delivery system to alter the level of the analyte based on the data obtained using the sensor.

RELATED APPLICATIONS

[0001] This application is a continuation of pending application Ser.No. 10/420,054 filed Apr. 18, 2003 which is a continuation ofapplication Ser. No. 09/667,199 filed Sep. 21, 2000, now U.S. Pat. No.6,565,509 B1, which is a continuation of application Ser. No. 09/070,677filed Apr. 30, 1998 now U.S. Pat. No. 6,175,752 B1, the disclosure ofeach of which are incorporated herein by reference for all purposes, andeach of which are assigned to assignee, TheraSense, Inc., of Alameda,Calif.

FIELD OF THE INVENTION

[0002] The present invention is, in general, directed to devices andmethods for the in vivo monitoring of an analyte, such as glucose orlactate. More particularly, the present invention relates to devices andmethods for the in vivo monitoring of an analyte using anelectrochemical sensor to provide information to a patient about thelevel of the analyte.

BACKGROUND OF THE INVENTION

[0003] The monitoring of the level of glucose of other analytes, such aslactate or oxygen, in certain individuals is vitally important to theirhealth. High or low levels of glucose or other analytes may be havedetrimental effects. The monitoring of glucose is particularly importantto individuals with diabetes, as they must determine when insulin isneeded to reduce glucose levels in their bodies or when additionalglucose is needed to raise the level of glucose in their bodies.

[0004] A conventional technique used by many diabetics for personallymonitoring their blood glucose level includes the periodic drawing ofblood, the application of that blood to a test strip, and thedetermination of the blood glucose level using calorimetric,electrochemical, or photometric detection. This technique does notpermit continuous or automatic monitoring of glucose levels in the body,but typically must be performed manually on a periodic basis.Unfortunately, the consistency with which the level of glucose ischecked varies widely among individuals. Many diabetics find theperiodic testing inconvenient and they sometimes forget to test theirglucose level or do not have time for a proper test. In addition, someindividuals wish to avoid the pain associated with the test. Thesesituations may result in hyperglycemic or hypoglycemic episodes.

[0005] An in vivo glucose sensor that continuously or automaticallymonitors the individual's glucose level would enable individuals to moreeasily monitor their glucose, or other analyte, levels.

[0006] A variety of devices have been developed for continuous orautomatic monitoring of analytes, such as glucose, in the blood streamor interstitial fluid. A number of these devices use electrochemicalsensors which are directly implanted into a blood vessel or in thesubcutaneous tissue of a patient. However, these devices are oftendifficult to reproducibly and inexpensively manufacture in largenumbers. In addition, these devices are typically large, bulky, and/orinflexible, and many can not be used effectively outside of a controlledmedical facility, such as a hospital or a doctor's office, unless thepatient is restricted in his activities.

[0007] Some devices include a sensor guide which rests on or near theskin of the patient and may be attached to the patient to hold thesensor in place. These sensor guides are typically bulky and do notallow for freedom of movement. In addition, the sensor guides or thesensors include cables or wires for connecting the sensor to otherequipment to direct the signals from the sensors to an analyzer. Thesize of the sensor guides and presence of cables and wires hinders theconvenient use of these devices for everyday applications. There is aneed for a small, compact device that can operate the sensor and providesignals to an analyzer without substantially restricting the movementsand activities of a patient.

[0008] The patient's comfort and the range of activities that can beperformed while the sensor is implanted are important considerations indesigning extended-use sensors for continuous or automatic in vivomonitoring of the level of an analyte, such as glucose. There is a needfor a small, comfortable device which can continuously monitor the levelof an analyte, such as glucose, while still permitting the patient toengage in normal activities. Continuous and/or automatic monitoring ofthe analyte can provide a warning to the patient when the level of theanalyte is at or near a threshold level. For example, if glucose is theanalyte, then the monitoring device might be configured to warn thepatient of current or impending hyperglycemia or hypoglycemia. Thepatient can then take appropriate actions.

SUMMARY OF THE INVENTION

[0009] Generally, the present invention relates to methods and devicesfor the continuous and/or automatic in vivo monitoring of the level ofan analyte using a subcutaneously implantable sensor. Many of thesedevices are small and comfortable when used, thereby allowing a widerange of activities. One embodiment is a sensor control unit having ahousing adapted for placement on skin. The housing is also adapted toreceive a portion of an electrochemical sensor. The sensor control unitincludes two or more conductive contacts disposed on the housing andconfigured for coupling to two or more contact pads on the sensor. Atransmitter is disposed in the housing and coupled to the plurality ofconductive contacts for transmitting data obtained using the sensor. Thesensor control unit may also include a variety of optional components,such as, for example, adhesive for adhering to the skin, a mountingunit, a receiver, a processing circuit, a power supply (e.g., abattery), an alarm system, a data storage unit, a watchdog circuit, anda measurement circuit. Other optional components are described below.

[0010] Another embodiment of the invention is a sensor assembly thatincludes the sensor control unit described above. The sensor assemblyalso includes a sensor having at least one working electrode and atleast one contact pad coupled to the working electrode or electrodes.The sensor may also include optional components, such as, for example, acounter electrode, a counter/reference electrode, a reference electrode,and a temperature probe. Other components and options for the sensor aredescribed below.

[0011] A further embodiment of the invention is an analyte monitoringsystem that includes the sensor control unit described above. Theanalyte monitoring system also includes a sensor that has at least oneworking electrode and at least one contact pad coupled to the workingelectrode or electrodes. The analyte monitoring system also includes adisplay unit that has a receiver for receiving data from the sensorcontrol unit and a display coupled to the receiver for displaying anindication of the level of an analyte. The display unit may optionallyinclude a variety of components, such as, for example, a transmitter, ananalyzer, a data storage unit, a watchdog circuit, an input device, apower supply, a clock, a lamp, a pager, a telephone interface, acomputer interface, an alarm or alarm system, a radio, and a calibrationunit. Further components and options for the display unit are describedbelow. In addition, the analyte monitoring system or a component of theanalyte monitoring system may optionally include a processor capable ofdetermining a drug or treatment protocol and/or a drug delivery system.

[0012] Yet another embodiment of the invention is an insertion kit forinserting an electrochemical sensor into a patient. The insertion kitincludes an inserter. A portion of the inserter has a sharp, rigid,planer structure adapted to support the sensor during insertion of theelectrochemical sensor. The insertion kit also includes an insertion gunhaving a port configured to accept the electrochemical sensor and theinserter. The insertion gun has a driving mechanism for driving theinserter and electrochemical sensor into the patient, and a retractionmechanism for removing the inserter while leaving the sensor within thepatient.

[0013] Another embodiment is a method of using an electrochemicalsensor. A mounting unit is adhered to skin of a patient. An insertiongun is aligned with a port on the mounting unit. The electrochemicalsensor is disposed within the insertion gun and then the electrochemicalsensor is inserted into the skin of the patient using the insertion gun.The insertion gun is removed and a housing of the sensor control unit ismounted on the mounting base. A plurality of conductive contactsdisposed on the housing is coupled to a plurality of contact padsdisposed on the electrochemical sensor to prepare the sensor for use.

[0014] One embodiment of the invention is a method for detectingfailures in an implanted analyte-responsive sensor. Ananalyte-responsive sensor is implanted into a patient. Theanalyte-responsive sensor includes N working electrodes, where N is aninteger and is two or greater, and a common counter electrode. Signalsgenerated at one of the N working electrodes and at the common counterelectrode are then obtained and the sensor is determined to have failedif the signal from the common counter electrode is not N times thesignal from one of the working electrodes, within a predeterminedthreshold limit.

[0015] Yet another embodiment is a method of calibrating anelectrochemical sensor having one or more working electrodes implantedin a patient. A signal is generated from each of the working electrodes.Several conditions are tested to determine if calibration isappropriate. First, the signals from each of the one or more workingelectrodes should differ by less than a first threshold amount. Second,the signals from each of the one or more working electrodes should bewithin a predetermined range. And, third, a rate of change of thesignals from each of the one or more working electrodes should be lessthan a second threshold amount. A calibration value is found assaying acalibration sample of a patient's body fluid. The calibration value isthen related to at least one of the signals from the one or more workingelectrodes if the conditions described above are met.

[0016] A further embodiment is a method for monitoring a level of ananalyte. A sensor is inserted into a skin of a patient and a sensorcontrol unit is attached to the skin of the patient. Two or moreconductive contacts on the sensor control unit are coupled to contactpads on the sensor. Then, using the sensor control unit, data iscollected regarding a level of an analyte from signals generated by thesensor. The collected data is transmitted to a display unit and anindication of the level of the analyte is displayed on the display unit.

[0017] The above summary of the present invention is not intended todescribe each disclosed embodiment or every implementation of thepresent invention. The Figures and the detailed description which followmore particularly exemplify these embodiments.

BRIEF DESCRIPTION OF THE DRAWINGS

[0018] The invention may be more completely understood in considerationof the following detailed description of various embodiments of theinvention in connection with the accompanying drawings, in which:

[0019]FIG. 1 is a block diagram of one embodiment of a subcutaneousanalyte monitor using a subcutaneously implantable analyte sensor,according to the invention;

[0020]FIG. 2 is a top view of one embodiment of an analyte sensor,according to the invention;

[0021]FIG. 3A is a cross-sectional view of the analyte sensor of FIG. 2;

[0022]FIG. 3B is a cross-sectional view of another embodiment of ananalyte sensor, according to the invention;

[0023]FIG. 4A is a cross-sectional view of a third embodiment of ananalyte sensor, according to the invention;

[0024]FIG. 4B is a cross-sectional view of a fourth embodiment of ananalyte sensor, according to the invention;

[0025]FIG. 5 is an expanded top view of a tip portion of the analytesensor of FIG. 2;

[0026]FIG. 6 is a cross-sectional view of a fifth embodiment of ananalyte sensor, according to the invention;

[0027]FIG. 7 is an expanded top view of a tip-portion of the analytesensor of FIG. 6;

[0028]FIG. 8 is an expanded bottom view of a tip-portion of the analytesensor of FIG. 6;

[0029]FIG. 9 is a side view of the analyte sensor of FIG. 2;

[0030]FIG. 10 is a top view of the analyte sensor of FIG. 6;

[0031]FIG. 11 is a bottom view of the analyte sensor of FIG. 6;

[0032]FIG. 12 is an expanded side view of one embodiment of a sensor andan insertion device, according to the invention;

[0033]FIGS. 13A, 13B, 13C are cross-sectional views of three embodimentsof the insertion device of FIG. 12;

[0034]FIG. 14 is a cross-sectional view of one embodiment of a on-skinsensor control unit, according to the invention;

[0035]FIG. 15 is a top view of a base of the on-skin sensor control unitof FIG. 14;

[0036]FIG. 16 is a bottom view of a cover of the on-skin sensor controlunit of FIG. 14;

[0037]FIG. 17 is a perspective view of the on-skin sensor control unitof FIG. 14 on the skin of a patient;

[0038]FIG. 18A is a block diagram of one embodiment of an on-skin sensorcontrol unit, according to the invention;

[0039]FIG. 18B is a block diagram of another embodiment of an on-skinsensor control unit, according to the invention;

[0040]FIGS. 19A, 19B, 19C, and 19D are cross-sectional views of fourembodiments of conductive contacts disposed on an interior surface of ahousing of an on-skin sensor control unit, according to the invention;

[0041]FIGS. 19E and 19F are cross-sectional views of two embodiments ofconductive contacts disposed on an exterior surface of a housing of anon-skin sensor control unit, according to the invention;

[0042]FIGS. 20A and 20B are schematic diagrams of two embodiments of acurrent-to-voltage converter for use in an analyte monitoring device,according to the invention;

[0043]FIG. 21 is a block diagram of one embodiment of an open loopmodulation system for use in an analyte monitoring device, according tothe invention;

[0044]FIG. 22 is a block diagram of one embodiment of a receiver/displayunit, according to the invention;

[0045]FIG. 23 is a front view of one embodiment of a receiver/displayunit;

[0046]FIG. 24 is a front view of a second embodiment of areceiver/display unit;

[0047]FIG. 25 is a block diagram of one embodiment of a drug deliverysystem, according to the invention;

[0048]FIG. 26 is a perspective view of the internal structure of aninsertion gun, according to the invention;

[0049]FIG. 27A is a top view of one embodiment of an on-skin sensorcontrol unit, according to the invention;

[0050]FIG. 27B is a top view of one embodiment of a mounting unit of theon-skin sensor control unit of FIG. 27A;

[0051]FIG. 28A is a top view of another embodiment of an on-skin sensorcontrol unit after insertion of an insertion device and a sensor,according to the invention;

[0052]FIG. 28B is a top view of one embodiment of a mounting unit of theon-skin sensor control unit of FIG. 28A;

[0053]FIG. 28C is a top view of one embodiment of a housing for at leasta portion of the electronics of the on-skin sensor control unit of FIG.28A;

[0054]FIG. 28D is a bottom view of the housing of FIG. 28C; and

[0055]FIG. 28E is a top view of the on-skin sensor control unit of FIG.28A with a cover of the housing removed.

[0056] While the invention is amenable to various modifications andalternative forms, specifics thereof have been shown by way of examplein the drawings and will be described in detail. It should beunderstood, however, that the intention is not to limit the invention tothe particular embodiments described. On the contrary, the intention isto cover all modifications, equivalents, and alternatives falling withinthe spirit and scope of the invention as defined by the appended claims.

DETAILED DESCRIPTION OF THE INVENTION

[0057] The present invention is applicable to an analyte monitoringsystem using an implantable sensor for the in vivo determination of aconcentration of an analyte, such as glucose or lactate, in a fluid. Thesensor can be, for example, subcutaneously implanted in a patient forthe continuous or periodic monitoring an analyte in a patient'sinterstitial fluid. This can then be used to infer the glucose level inthe patient's bloodstream. Other in vivo analyte sensors can be made,according to the invention, for insertion into a vein, artery, or otherportion of the body containing fluid. The analyte monitoring system istypically configured for monitoring the level of the analyte over a timeperiod which may range from days to weeks or longer.

[0058] The following definitions are provided for terms used herein:

[0059] A “counter electrode” refers to an electrode paired with theworking electrode, through which passes a current equal in magnitude andopposite in sign to the current passing through the working electrode.In the context of the invention, the term “counter electrode” is meantto include counter electrodes which also function as referenceelectrodes (i.e., a counter/reference electrode).

[0060] An “electrochemical sensor” is a device configured to detect thepresence and/or measure the level of an analyte in a sample viaelectrochemical oxidation and reduction reactions on the sensor. Thesereactions are transduced to an electrical signal that can be correlatedto an amount, concentration, or level of an analyte in the sample.

[0061] “Electrolysis” is the electrooxidation or electroreduction of acompound either directly at an electrode or via one or more electrontransfer agents.

[0062] A compound is “immobilized” on a surface when it is entrapped onor chemically bound to the surface.

[0063] A “non-leachable” or “non-releasable” compound or a compound thatis “non-leachably disposed” is meant to define a compound that isaffixed on the sensor such that it does not substantially diffuse awayfrom the working surface of the working electrode for the period inwhich the sensor is used (e.g., the period in which the sensor isimplanted in a patient or measuring a sample).

[0064] Components are “immobilized” within a sensor, for example, whenthe components are covalently, ionically, or coordinatively bound toconstituents of the sensor and/or are entrapped in a polymeric orsol-gel matrix or membrane which precludes mobility.

[0065] An “electron transfer agent” is a compound that carries electronsbetween the analyte and the working electrode, either directly, or incooperation with other electron transfer agents. One example of anelectron transfer agent is a redox mediator.

[0066] A “working electrode” is an electrode at which the analyte (or asecond compound whose level depends on the level of the analyte) iselectrooxidized or electroreduced with or without the agency of anelectron transfer agent.

[0067] A “working surface” is that portion of the working electrodewhich is coated with or is accessible to the electron transfer agent andconfigured for exposure to an analyte-containing fluid.

[0068] A “sensing layer” is a component of the sensor which includesconstituents that facilitate the electrolysis of the analyte. Thesensing layer may include constituents such as an electron transferagent, a catalyst which catalyzes a reaction of the analyte to produce aresponse at the electrode, or both. In some embodiments of the sensor,the sensing layer is non-leachably disposed in proximity to or on theworking electrode.

[0069] A “non-corroding” conductive material includes non-metallicmaterials, such as carbon and conductive polymers.

[0070] Analyte Sensor Systems

[0071] The analyte monitoring systems of the present invention can beutilized under a variety of conditions. The particular configuration ofa sensor and other units used in the analyte monitoring system maydepend on the use for which the analyte monitoring system is intendedand the conditions under which the analyte monitoring system willoperate. One embodiment of the analyte monitoring system includes asensor configured for implantation into a patient or user. For example,implantation of the sensor may be made in the arterial or venous systemsfor direct testing of analyte levels in blood. Alternatively, a sensormay be implanted in the interstitial tissue for determining the analytelevel in interstitial fluid. This level may be correlated and/orconverted to analyte levels in blood or other fluids. The site and depthof implantation may affect the particular shape, components, andconfiguration of the sensor. Subcutaneous implantation may be preferred,in some cases, to limit the depth of implantation of the sensor. Sensorsmay also be implanted in other regions of the body to determine analytelevels in other fluids. Examples of suitable sensor for use in theanalyte monitoring systems of the invention are described in U.S. patentapplication Ser. No. 09/034,372, incorporated herein by reference.

[0072] One embodiment of the analyte monitoring system 40 for use withan implantable sensor 42, and particularly for use with a subcutaneouslyimplantable sensor, is illustrated in block diagram form in FIG. 1. Theanalyte monitoring system 40 includes, at minimum, a sensor 42, aportion of which is configured for implantation (e.g., subcutaneous,venous, or arterial implantation) into a patient, and a sensor controlunit 44. The sensor 42 is coupled to the sensor control unit 44 which istypically attached to the skin of a patient. The sensor control unit 44operates the sensor 42, including, for example, providing a voltageacross the electrodes of the sensor 42 and collecting signals from thesensor 42. The sensor control unit 44 may evaluate the signals from thesensor 42 and/or transmit the signals to one or more optionalreceiver/display units 46, 48 for evaluation. The sensor control unit 44and/or the receiver/display units 46, 48 may display or otherwisecommunicate the current level of the analyte. Furthermore, the sensorcontrol unit 44 and/or the receiver/display units 46, 48 may indicate tothe patient, via, for example, an audible, visual, or othersensory-stimulating alarm, when the level of the analyte is at or near athreshold level. In some embodiments, a electrical shock can bedelivered to the patient as a warning through one of the electrodes orthe optional temperature probe of the sensor. For example, if glucose ismonitored then an alarm may be used to alert the patient to ahypoglycemic or hyperglycemic glucose level and/or to impendinghypoglycemia or hyperglycemia.

[0073] The Sensor

[0074] A sensor 42 includes at least one working electrode 58 formed ona substrate 50, as shown in FIG. 2. The sensor 42 may also include atleast one counter electrode 60 (or counter/reference electrode) and/orat least one reference electrode 62 (see FIG. 8). The counter electrode60 and/or reference electrode 62 may be formed on the substrate 50 ormay be separate units. For example, the counter electrode and/orreference electrode may be formed on a second substrate which is alsoimplanted in the patient or, for some embodiments of the implantablesensors, the counter electrode and/or reference electrode may be placedon the skin of the patient with the working electrode or electrodesbeing implanted into the patient. The use of an on-the-skin counterand/or reference electrode with an implantable working electrode isdescribed in U.S. Pat. No. 5,593,852, incorporated herein by reference.

[0075] The working electrode or electrodes 58 are formed usingconductive traces 52 disposed on the substrate 50. The counter electrode60 and/or reference electrode 62, as well as other optional portions ofthe sensor 42, such as a temperature probe 66 (see FIG. 8), may also beformed using conductive traces 52 disposed on the substrate 50. Theseconductive traces 52 may be formed over a smooth surface of thesubstrate 50 or within channels 54 formed by, for example, embossing,indenting or otherwise creating a depression in the substrate 50.

[0076] A sensing layer 64 (see FIGS. 3A and 3B) is often formedproximate to or on at least one of the working electrodes 58 tofacilitate the electrochemical detection of the analyte and thedetermination of its level in the sample fluid, particularly if theanalyte can not be electrolyzed at a desired rate and/or with a desiredspecificity on a bare electrode. The sensing layer 64 may include anelectron transfer agent to transfer electrons directly or indirectlybetween the analyte and the working electrode 58. The sensing layer 64may also contain a catalyst to catalyze a reaction of the analyte. Thecomponents of the sensing layer may be in a fluid or gel that isproximate to or in contact with the working electrode 58. Alternatively,the components of the sensing layer 64 may be disposed in a polymeric orsol-gel matrix that is proximate to or on the working electrode 58.Preferably, the components of the sensing layer 64 are non-leachablydisposed within the sensor 42. More preferably, the components of thesensor 42 are immobilized within the sensor 42.

[0077] In addition to the electrodes 58, 60, 62 and the sensing layer64, the sensor 42 may also include a temperature probe 66 (see FIGS. 6and 8), a mass transport limiting layer 74 (see FIG. 9), a biocompatiblelayer 75 (see FIG. 9), and/or other optional components, as describedbelow. Each of these items enhances the functioning of and/or resultsfrom the sensor 42, as discussed below.

[0078] The Substrate

[0079] The substrate 50 may be formed using a variety of non-conductingmaterials, including, for example, polymeric or plastic materials andceramic materials. Suitable materials for a particular sensor 42 may bedetermined, at least in part, based on the desired use of the sensor 42and properties of the materials.

[0080] In some embodiments, the substrate is flexible. For example, ifthe sensor 42 is configured for implantation into a patient, then thesensor 42 may be made flexible (although rigid sensors may also be usedfor implantable sensors) to reduce pain to the patient and damage to thetissue caused by the implantation of and/or the wearing of the sensor42. A flexible substrate 50 often increases the patient's comfort andallows a wider range of activities. Suitable materials for a flexiblesubstrate 50 include, for example, non-conducting plastic or polymericmaterials and other non-conducting, flexible, deformable materials.Examples of useful plastic or polymeric materials include thermoplasticssuch as polycarbonates, polyesters (e.g., Mylar™ and polyethyleneterephthalate (PET)), polyvinyl chloride (PVC), polyurethanes,polyethers, polyamides, polyimides, or copolymers of thesethermoplastics, such as PETG (glycol-modified polyethyleneterephthalate).

[0081] In other embodiments, the sensors 42 are made using a relativelyrigid substrate 50 to for example, provide structural support againstbending or breaking. Examples of rigid materials that may be used as thesubstrate 50 include poorly conducting ceramics, such as aluminum oxideand silicon dioxide. One advantage of an implantable sensor 42 having arigid substrate is that the sensor 42 may have a sharp point and/or asharp edge to aid in implantation of a sensor 42 without an additionalinsertion device.

[0082] It will be appreciated that for many sensors 42 and sensorapplications, both rigid and flexible sensors will operate adequately.The flexibility of the sensor 42 may also be controlled and varied alonga continuum by changing, for example, the composition and/or thicknessof the substrate 50.

[0083] In addition to considerations regarding flexibility, it is oftendesirable that implantable sensors 42 should have a substrate 50 whichis non-toxic. Preferably, the substrate 50 is approved by one or moreappropriate governmental agencies or private groups for in vivo use.

[0084] The sensor 42 may include optional features to facilitateinsertion of an implantable sensor 42, as shown in FIG. 12. For example,the sensor 42 may be pointed at the tip 123 to ease insertion. Inaddition, the sensor 42 may include a barb 125 which assists inanchoring the sensor 42 within the tissue of the patient duringoperation of the sensor 42. However, the barb 125 is typically smallenough that little damage is caused to the subcutaneous tissue when thesensor 42 is removed for replacement.

[0085] Although the substrate 50 in at least some embodiments hasuniform dimensions along the entire length of the sensor 42, in otherembodiments, the substrate 50 has a distal end 67 and a proximal end 65with different widths 53, 55, respectively, as illustrated in FIG. 2. Inthese embodiments, the distal end 67 of the substrate 50 may have arelatively narrow width 53. For sensors 42 which are implantable intothe subcutaneous tissue or another portion of a patient's body, thenarrow width 53 of the distal end 67 of the substrate 50 may facilitatethe implantation of the sensor 42. Often, the narrower the width of thesensor 42, the less pain the patient will feel during implantation ofthe sensor and afterwards.

[0086] For subcutaneously implantable sensors 42 which are designed forcontinuous or periodic monitoring of the analyte during normalactivities of the patient, a distal end 67 of the sensor 42 which is tobe implanted into the patient has a width 53 of 2 mm or less, preferably1 mm or less, and more preferably 0.5 mm or less. If the sensor 42 doesnot have regions of different widths, then the sensor 42 will typicallyhave an overall width of, for example, 2 mm, 1.5 mm, 1 mm, 0.5 mm, 0.25mm, or less. However, wider or narrower sensors may be used. Inparticular, wider implantable sensors may be used for insertion intoveins or arteries or when the movement of the patient is limited, forexample, when the patient is confined in bed or in a hospital.

[0087] Returning to FIG. 2, the proximal end 65 of the sensor 42 mayhave a width 55 larger than the distal end 67 to facilitate theconnection between contact pads 49 of the electrodes and contacts on acontrol unit. The wider the sensor 42 at this point, the larger thecontact pads 49 can be made. This may reduce the precision needed toproperly connect the sensor 42 to contacts on the control unit (e.g.,sensor control unit 44 of FIG. 1). However, the maximum width of thesensor 42 may be constrained so that the sensor 42 remains small for theconvenience and comfort of the patient and/or to fit the desired size ofthe analyte monitor. For example, the proximal end 65 of asubcutaneously implantable sensor 42, such as the sensor 42 illustratedin FIG. 1, may have a width 55 ranging from 0.5 mm to 15 mm, preferablyfrom 1 mm to 10 mm, and more preferably from 3 mm to 7 mm. However,wider or narrower sensors may be used in this and other in vivoapplications.

[0088] The thickness of the substrate 50 may be determined by themechanical properties of the substrate material (e.g., the strength,modulus, and/or flexibility of the material), the desired use of thesensor 42 including stresses on the substrate 50 arising from that use,as well as the depth of any channels or indentations formed in thesubstrate 50, as discussed below. Typically, the substrate 50 of asubcutaneously implantable sensor 42 for continuous or periodicmonitoring of the level of an analyte while the patient engages innormal activities has a thickness of 50 to 500 μm and preferably 100 to300 μm. However, thicker and thinner substrates 50 may be used,particularly in other types of in vivo sensors 42.

[0089] The length of the sensor 42 may have a wide range of valuesdepending on a variety of factors. Factors which influence the length ofan implantable sensor 42 may include the depth of implantation into thepatient and the ability of the patient to manipulate a small flexiblesensor 42 and make connections between the sensor 42 and the sensorcontrol unit 44. A subcutaneously implantable sensor 42 for the analytemonitor illustrated in FIG. 1 may have a length ranging from 0.3 to 5cm, however, longer or shorter sensors may be used. The length of thenarrow portion of the sensor 42 (e.g., the portion which issubcutaneously inserted into the patient), if the sensor 42 has narrowand wide portions, is typically about 0.25 to 2 cm in length. However,longer and shorter portions may be used. All or only a part of thisnarrow portion may be subcutaneously implanted into the patient. Thelengths of other implantable sensors 42 will vary depending, at least inpart, on the portion of the patient into which the sensor 42 is to beimplanted or inserted.

[0090] Conductive Traces

[0091] At least one conductive trace 52 is formed on the substrate foruse in constructing a working electrode 58. In addition, otherconductive traces 52 may be formed on the substrate 50 for use aselectrodes (e.g., additional working electrodes, as well as counter,counter/reference, and/or reference electrodes) and other components,such as a temperature probe. The conductive traces 52 may extend most ofthe distance along a length 57 of the sensor 50, as illustrated in FIG.2, although this is not necessary. The placement of the conductivetraces 52 may depend on the particular configuration of the analytemonitoring system (e.g., the placement of control unit contacts and/orthe sample chamber in relation to the sensor 42). For implantablesensors, particularly subcutaneously implantable sensors, the conductivetraces typically extend close to the tip of the sensor 42 to minimizethe amount of the sensor that must be implanted.

[0092] The conductive traces 52 may be formed on the substrate 50 by avariety of techniques, including, for example, photolithography, screenprinting, or other impact or non-impact printing techniques. Theconductive traces 52 may also be formed by carbonizing conductive traces52 in an organic (e.g., polymeric or plastic) substrate 50 using alaser. A description of some exemplary methods for forming the sensor 42is provided in U.S. patent application Ser. No. 09/034,422, incorporatedherein by reference.

[0093] Another method for disposing the conductive traces 52 on thesubstrate 50 includes the formation of recessed channels 54 in one ormore surfaces of the substrate 50 and the subsequent filling of theserecessed channels 54 with a conductive material 56, as shown in FIG. 3A.The recessed channels 54 may be formed by indenting, embossing, orotherwise creating a depression in the surface of the substrate 50.Exemplary methods for forming channels and electrodes in a surface of asubstrate can be found in U.S. patent application Ser. No. 09/034,422.The depth of the channels is typically related to the thickness of thesubstrate 50. In one embodiment, the channels have depths in the rangeof about 12.5 to 75 μm (0.5 to 3 mils), and preferably about 25 to 50 μm(1 to 2 mils).

[0094] The conductive traces are typically formed using a conductivematerial 56 such as carbon (e.g., graphite), a conductive polymer, ametal or alloy (e.g., gold or gold alloy), or a metallic compound (e.g.,ruthenium dioxide or titanium dioxide). The formation of films ofcarbon, conductive polymer, metal, alloy, or metallic compound arewell-known and include, for example, chemical vapor deposition (CVD),physical vapor deposition, sputtering, reactive sputtering, printing,coating, and painting. The conductive material 56 which fills thechannels 54 is often formed using a precursor material, such as aconductive ink or paste. In these embodiments, the conductive material56 is deposited on the substrate 50 using methods such as coating,painting, or applying the material using a spreading instrument, such asa coating blade. Excess conductive material between the channels 54 isthen removed by, for example, running a blade along the substratesurface.

[0095] In one embodiment, the conductive material 56 is a part of aprecursor material, such as a conductive ink, obtainable, for example,from Ercon, Inc. (Wareham, Mass.), Metech, Inc. (Elverson, Pa.), E.I. duPont de Nemours and Co. (Wilmington, Del.), Emca-Remex Products(Montgomeryville, Pa.), or MCA Services (Melbourn, Great Britain). Theconductive ink is typically applied as a semiliquid or paste whichcontains particles of the carbon, metal, alloy, or metallic compound anda solvent or dispersant. After application of the conductive ink on thesubstrate 50 (e.g., in the channels 54), the solvent or dispersantevaporates to leave behind a solid mass of conductive material 56.

[0096] In addition to the particles of carbon, metal, alloy, or metalliccompound, the conductive ink may also contain a binder. The binder mayoptionally be cured to further bind the conductive material 56 withinthe channel 54 and/or on the substrate 50. Curing the binder increasesthe conductivity of the conductive material 56. However, this istypically not necessary as the currents carried by the conductivematerial 56 within the conductive traces 52 are often relatively low(usually less than 1 μA and often less than 100 nA). Typical bindersinclude, for example, polyurethane resins, cellulose derivatives,elastomers, and highly fluorinated polymers. Examples of elastomersinclude silicones, polymeric dienes, and acrylonitrile-butadiene-styrene(ABS) resins. One example of a fluorinated polymer binder is Teflon®(DuPont, Wilmington, Del.). These binders are cured using, for example,heat or light, including ultraviolet (UV) light. The appropriate curingmethod typically depends on the particular binder which is used.

[0097] Often, when a liquid or semiliquid precursor of the conductivematerial 56 (e.g., a conductive ink) is deposited in the channel 54, theprecursor fills the channel 54. However, when the solvent or dispersantevaporates, the conductive material 56 which remains may lose volumesuch that the conductive material 56 may or may not continue to fill thechannel 54. Preferred conductive materials 56 do not pull away from thesubstrate 50 as they lose volume, but rather decrease in height withinthe channel 54. These conductive materials 56 typically adhere well tothe substrate 50 and therefore do not pull away from the substrate 50during evaporation of the solvent or dispersant. Other suitableconductive materials 56 either adhere to at least a portion of thesubstrate 50 and/or contain another additive, such as a binder, whichadheres the conductive material 56 to the substrate 50. Preferably, theconductive material 56 in the channels 54 is non-leachable, and morepreferably immobilized on the substrate 50. In some embodiments, theconductive material 56 may be formed by multiple applications of aliquid or semiliquid precursor interspersed with removal of the solventor dispersant.

[0098] In another embodiment, the channels 54 are formed using a laser.The laser carbonizes the polymer or plastic material. The carbon formedin this process is used as the conductive material 56. Additionalconductive material 56, such as a conductive carbon ink, may be used tosupplement the carbon formed by the laser.

[0099] In a further embodiment, the conductive traces 52 are formed bypad printing techniques. For example, a film of conductive material isformed either as a continuous film or as a coating layer deposited on acarrier film. This film of conductive material is brought between aprint head and the substrate 50. A pattern on the surface of thesubstrate 50 is made using the print head according to a desired patternof conductive traces 52. The conductive material is transferred bypressure and/or heat from the film of conductive material to thesubstrate 50. This technique often produces channels (e.g., depressionscaused by the print head) in the substrate 50. Alternatively, theconductive material is deposited on the surface of the substrate 50without forming substantial depressions.

[0100] In other embodiments, the conductive traces 52 are formed bynon-impact printing techniques. Such techniques includeelectrophotography and magnetography. In these processes, an image ofthe conductive traces 52 is electrically or magnetically formed on adrum. A laser or LED may be used to electrically form an image. Amagnetic recording head may be used to magnetically form an image. Atoner material (e.g., a conductive material, such as a conductive ink)is then attracted to portions of the drum according to the image. Thetoner material is then applied to the substrate by contact between thedrum and the substrate. For example, the substrate may be rolled overthe drum. The toner material may then be dried and/or a binder in thetoner material may be cured to adhere the toner material to thesubstrate.

[0101] Another non-impact printing technique includes ejecting dropletsof conductive material onto the substrate in a desired pattern. Examplesof this technique include ink jet printing and piezo jet printing. Animage is sent to the printer which then ejects the conductive material(e.g., a conductive ink) according to the pattern. The printer mayprovide a continuous stream of conductive material or the printer mayeject the conductive material in discrete amounts at the desired points.

[0102] Yet another non-impact printing embodiment of forming theconductive traces includes an ionographic process. In the this process,a curable, liquid precursor, such as a photopolymerizable acrylic resin(e.g., Solimer 7501 from Cubital, Bad Kreuznach, Germany) is depositedover a surface of a substrate 50. A photomask having a positive ornegative image of the conductive traces 52 is then used to cure theliquid precursor. Light (e.g., visible or ultraviolet light) is directedthrough the photomask to cure the liquid precursor and form a solidlayer over the substrate according to the image on the photomask.Uncured liquid precursor is removed leaving behind channels 54 in thesolid layer. These channels 54 can then be filled with conductivematerial 56 to form conductive traces 52.

[0103] Conductive traces 52 (and channels 54, if used) can be formedwith relatively narrow widths, for example, in the range of 25 to 250μm, and including widths of, for example, 250 μm, 150 μm, 100 μm, 75 μm,50 μm, 25 μm or less by the methods described above. In embodiments withtwo or more conductive traces 52 on the same side of the substrate 50,the conductive traces 52 are separated by distances sufficient toprevent conduction between the conductive traces 52. The edge-to-edgedistance between the conductive traces is preferably in the range of 25to 250 μm and may be, for example, 150 μm, 100 μm, 751 μm, 50 μm, orless. The density of the conductive traces 52 on the substrate 50 ispreferably in the range of about 150 to 700 μm/trace and may be as smallas 667 μm/trace or less, 333 μm/trace or less, or even 167 μm/trace orless.

[0104] The working electrode 58 and the counter electrode 60 (if aseparate reference electrode is used) are often made using a conductivematerial 56, such as carbon. Suitable carbon conductive inks areavailable from Ercon, Inc. (Wareham, Mass.), Metech, Inc. (Elverson,Pa.), E.I. du Pont de Nemours and Co. (Wilmington, Del.), Emca-RemexProducts (Montgomeryville, Pa.), or MCA Services (Melbourn, GreatBritain). Typically, the working surface 51 of the working electrode 58is at least a portion of the conductive trace 52 that is in contact withthe analyte-containing fluid (e.g., implanted in the patient).

[0105] The reference electrode 62 and/or counter/reference electrode aretypically formed using conductive material 56 that is a suitablereference material, for example silver/silver chloride or anon-leachable redox couple bound to a conductive material, for example,a carbon-bound redox couple. Suitable silver/silver chloride conductiveinks are available from Ercon, Inc. (Wareham, Mass.), Metech, Inc.(Elverson, Pa.), E.I. du Pont de Nemours and Co. (Wilmington, Del.),Emca-Remex Products (Montgomeryville, Pa.), or MCA Services (Melbourn,Great Britain). Silver/silver chloride electrodes illustrate a type ofreference electrode that involves the reaction of a metal electrode witha constituent of the sample or body fluid, in this case, Cl⁻.

[0106] Suitable redox couples for binding to the conductive material ofthe reference electrode include, for example, redox polymers (e.g.,polymers having multiple redox centers.) It is preferred that thereference electrode surface be non-corroding so that an erroneouspotential is not measured. Preferred conductive materials include lesscorrosive metals, such as gold and palladium. Most preferred arenon-corrosive materials including non-metallic conductors, such ascarbon and conducting polymers. A redox polymer can be adsorbed on orcovalently bound to the conductive material of the reference electrode,such as a carbon surface of a conductive trace 52. Non-polymeric redoxcouples can be similarly bound to carbon or gold surfaces.

[0107] A variety of methods may be used to immobilize a redox polymer onan electrode surface. One method is adsorptive immobilization. Thismethod is particularly useful for redox polymers with relatively highmolecular weights. The molecular weight of a polymer may be increased,for example, by cross-linking.

[0108] Another method for immobilizing the redox polymer includes thefunctionalization of the electrode surface and then the chemicalbonding, often covalently, of the redox polymer to the functional groupson the electrode surface. One example of this type of immobilizationbegins with a poly(4-vinylpyridine). The polymer's pyridine rings are,in part, complexed with a reducible/oxidizable species, such as[Os(bpy)₂Cl]^(+/2+) where bpy is 2,2′-bipyridine. Part of the pyridinerings are quaternized by reaction with 2-bromoethylamine. The polymer isthen crosslinked, for example, using a diepoxide, such as polyethyleneglycol diglycidyl ether.

[0109] Carbon surfaces can be modified for attachment of a redox speciesor polymer, for example, by electroreduction of a diazonium salt. As anillustration, reduction of a diazonium salt formed upon diazotization ofp-aminobenzoic acid modifies a carbon surface with phenylcarboxylic acidfunctional groups. These functional groups can then be activated by acarbodiimide, such as 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimidehydrochloride. The activated functional groups are then bound with aamine-functionalized redox couple, such as the quaternizedosmium-containing redox polymer described above or2-aminoethylferrocene, to form the redox couple.

[0110] Similarly, gold can be functionalized by an amine, such ascystamine. A redox couple such as[Os(bpy)₂(pyridine-4-carboxylate)Cl]^(0/+) is activated by1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride to form areactive O-acylisourea which reacts with the gold-bound amine to form anamide.

[0111] In one embodiment, in addition to using the conductive traces 52as electrodes or probe leads, two or more of the conductive traces 52 onthe substrate 50 are used to give the patient a mild electrical shockwhen, for example, the analyte level exceeds a threshold level. Thisshock may act as a warning or alarm to the patient to initiate someaction to restore the appropriate level of the analyte.

[0112] The mild electrical shock is produced by applying a potentialbetween any two conductive traces 52 that are not otherwise connected bya conductive path. For example, two of the electrodes 58, 60, 62 or oneelectrode 58, 60, 62 and the temperature probe 66 may be used to providethe mild shock. Preferably, the working electrode 58 and the referenceelectrode 62 are not used for this purpose as this may cause some damageto the chemical components on or proximate to the particular electrode(e.g., the sensing layer on the working electrode or the redox couple onthe reference electrode).

[0113] The current used to produce the mild shock is typically 0.1 to 1mA. Higher or lower currents may be used, although care should be takento avoid harm to the patient. The potential between the conductivetraces is typically 1 to 10 volts. However, higher or lower voltages maybe used depending, for example, on the resistance of the conductivetraces 52, the distance between the conductive traces 52 and the desiredamount of current. When the mild shock is delivered, potentials at theworking electrode 58 and across the temperature probe 66 may be removedto prevent harm to those components caused by unwanted conductionbetween the working electrode 58 (and/or temperature probe 66, if used)and the conductive traces 52 which provide the mild shock.

[0114] Contact Pads

[0115] Typically, each of the conductive traces 52 includes a contactpad 49. The contact pad 49 may simply be a portion of the conductivetrace 52 that is indistinguishable from the rest of the trace 52 exceptthat the contact pad 49 is brought into contact with the conductivecontacts of a control unit (e.g., the sensor control unit 44 of FIG. 1).More commonly, however, the contact pad 49 is a region of the conductivetrace 52 that has a larger width than other regions of the trace 52 tofacilitate a connection with the contacts on the control unit. By makingthe contact pads 49 relatively large as compared with the width of theconductive traces 52, the need for precise registration between thecontact pads 49 and the contacts on the control unit is less criticalthan with small contact pads.

[0116] The contact pads 49 are typically made using the same material asthe conductive material 56 of the conductive traces 52. However, this isnot necessary. Although metal, alloys, and metallic compounds may beused to form the contact pads 49, in some embodiments, it is desirableto make the contact pads 49 from a carbon or other non-metallicmaterial, such as a conducting polymer. In contrast to metal or alloycontact pads, carbon and other non-metallic contact pads are not easilycorroded if the contact pads 49 are in a wet, moist, or humidenvironment. Metals and alloys may corrode under these conditions,particularly if the contact pads 49 and contacts of the control unit aremade using different metals or alloys. However, carbon and non-metalliccontact pads 49 do not significantly corrode, even if the contacts ofthe control device are metal or alloy.

[0117] One embodiment of the invention includes a sensor 42 havingcontact pads 49 and a control unit 44 having conductive contacts (notshown). During operation of the sensor 42, the contact pads 49 andconductive contacts are in contact with each other. In this embodiment,either the contact pads 49 or the conductive contacts are made using anon-corroding, conductive material. Such materials include, for example,carbon and conducting polymers. Preferred non-corroding materialsinclude graphite and vitreous carbon. The opposing contact pad orconductive contact is made using carbon, a conducting polymer, a metal,such as gold, palladium, or platinum group metal, or a metalliccompound, such as ruthenium dioxide. This configuration of contact padsand conductive contacts typically reduces corrosion. Preferably, whenthe sensor is placed in a 3 mM, and more preferably, in a 100 mM, NaClsolution, the signal arising due to the corrosion of the contact padsand/or conductive contacts is less than 3% of the signal generated bythe sensor when exposed to concentration of analyte in the normalphysiological range. For at least some subcutaneous glucose sensors, thecurrent generated by analyte in a normal physiological range ranges from3 to 500 nA.

[0118] Each of the electrodes 58, 60, 62, as well as the two probe leads68, 70 of the temperature probe 66 (described below), are connected tocontact pads 49 as shown in FIGS. 10 and 11. In one embodiment (notshown), the contact pads 49 are on the same side of the substrate 50 asthe respective electrodes or temperature probe leads to which thecontact pads 49 are attached.

[0119] In other embodiments, the conductive traces 52 on at least oneside are connected through vias in the substrate to contact pads 49 a onthe opposite surface of the substrate 50, as shown in FIGS. 10 and 11.An advantage of this configuration is that contact between the contactson the control unit and each of the electrodes 58, 60, 62 and the probeleads 68,70 of the temperature probe 66 can be made from a single sideof the substrate 50.

[0120] In yet other embodiments (not shown), vias through the substrateare used to provide contact pads on both sides of the substrate 50 foreach conductive trace 52. The vias connecting the conductive traces 52with the contact pads 49 a can be formed by making holes through thesubstrate 50 at the appropriate points and then filling the holes withconductive material 56.

[0121] Exemplary Electrode Configurations

[0122] A number of exemplary electrode configurations are describedbelow, however, it will be understood that other configurations may alsobe used. In one embodiment, illustrated in FIG. 3A, the sensor 42includes two working electrodes 58 a, 58 b and one counter electrode 60,which also functions as a reference electrode. In another embodiment,the sensor includes one working electrode 58 a, one counter electrode60, and one reference electrode 62, as shown in FIG. 3B. Each of theseembodiments is illustrated with all of the electrodes formed on the sameside of the substrate 50.

[0123] Alternatively, one or more of the electrodes may be formed on anopposing side of the substrate 50. This may be convenient if theelectrodes are formed using two different types of conductive material56 (e.g., carbon and silver/silver chloride). Then, at least in someembodiments, only one type of conductive material 56 needs to be appliedto each side of the substrate 50, thereby reducing the number of stepsin the manufacturing process and/or easing the registration constraintsin the process. For example, if the working electrode 58 is formed usinga carbon-based conductive material 56 and the reference orcounter/reference electrode is formed using a silver/silver chlorideconductive material 56, then the working electrode and reference orcounter/reference electrode may be formed on opposing sides of thesubstrate 50 for ease of manufacture.

[0124] In another embodiment, two working electrodes 58 and one counterelectrode 60 are formed on one side of the substrate 50 and onereference electrode 62 and a temperature probe 66 are formed on anopposing side of the substrate 50, as illustrated in FIG. 6. Theopposing sides of the tip of this embodiment of the sensor 42 areillustrated in FIGS. 7 and 8.

[0125] Sensing Layer

[0126] Some analytes, such as oxygen, can be directly electrooxidized orelectroreduced on the working electrode 58. Other analytes, such asglucose and lactate, require the presence of at least one electrontransfer agent and/or at least one catalyst to facilitate theelectrooxidation or electroreduction of the analyte. Catalysts may alsobe used for those analyte, such as oxygen, that can be directlyelectrooxidized or electroreduced on the working electrode 58. For theseanalytes, each working electrode 58 has a sensing layer 64 formedproximate to or on a working surface of the working electrode 58.Typically, the sensing layer 64 is formed near or on only a smallportion of the working electrode 58, often near a tip of the sensor 42.This limits the amount of material needed to form the sensor 42 andplaces the sensing layer 64 in the best position for contact with theanalyte-containing fluid (e.g., a body fluid, sample fluid, or carrierfluid).

[0127] The sensing layer 64 includes one or more components designed tofacilitate the electrolysis of the analyte. The sensing layer 64 mayinclude, for example, a catalyst to catalyze a reaction of the analyteand produce a response at the working electrode 58, an electron transferagent to indirectly or directly transfer electrons between the analyteand the working electrode 58, or both.

[0128] The sensing layer 64 may be formed as a solid composition of thedesired components (e.g., an electron transfer agent and/or a catalyst).These components are preferably non-leachable from the sensor 42 andmore preferably are immobilized on the sensor 42. For example, thecomponents may be immobilized on a working electrode 58. Alternatively,the components of the sensing layer 64 may be immobilized within orbetween one or more membranes or films disposed over the workingelectrode 58 or the components may be immobilized in a polymeric orsol-gel matrix. Examples of immobilized sensing layers are described inU.S. Pat. Nos. 5,262,035, 5,264,104, 5,264,105, 5,320,725, 5,593,852,and 5,665,222, U.S. patent application Ser. No. 08/540,789, and PCTPatent Application No. US98/02403 entitled “Soybean PeroxidaseElectrochemical Sensor”, filed on Feb. 11, 1998, Attorney Docket No. M&G12008.8WOI2, incorporated herein by reference.

[0129] In some embodiments, one or more of the components of the sensinglayer 64 may be solvated, dispersed, or suspended in a fluid within thesensing layer 64, instead of forming a solid composition. The fluid maybe provided with the sensor 42 or may be absorbed by the sensor 42 fromthe analyte-containing fluid. Preferably, the components which aresolvated, dispersed, or suspended in this type of sensing layer 64 arenon-leachable from the sensing layer. Non-leachability may beaccomplished, for example, by providing barriers (e.g., the electrode,substrate, membranes, and/or films) around the sensing layer whichprevent the leaching of the components of the sensing layer 64. Oneexample of such a barrier is a microporous membrane or film which allowsdiffusion of the analyte into the sensing layer 64 to make contact withthe components of the sensing layer 64, but reduces or eliminates thediffusion of the sensing layer components (e.g., a electron transferagent and/or a catalyst) out of the sensing layer 64.

[0130] A variety of different sensing layer configurations can be used.In one embodiment, the sensing layer 64 is deposited on the conductivematerial 56 of a working electrode 58 a, as illustrated in FIGS. 3A and3B. The sensing layer 64 may extend beyond the conductive material 56 ofthe working electrode 58 a. In some cases, the sensing layer 64 may alsoextend over the counter electrode 60 or reference electrode 62 withoutdegrading the performance of the glucose sensor. For those sensors 42which utilize channels 54 within which the conductive material 56 isdeposited, a portion of the sensing layer 64 may be formed within thechannel 54 if the conductive material 56 does not fill the channel 54.

[0131] A sensing layer 64 in direct contact with the working electrode58 a may contain an electron transfer agent to transfer electronsdirectly or indirectly between the analyte and the working electrode, aswell as a catalyst to facilitate a reaction of the analyte. For example,a glucose, lactate, or oxygen electrode may be formed having a sensinglayer which contains a catalyst, such as glucose oxidase, lactateoxidase, or laccase, respectively, and an electron transfer agent thatfacilitates the electrooxidation of the glucose, lactate, or oxygen,respectively.

[0132] In another embodiment, the sensing layer 64 is not depositeddirectly on the working electrode 58 a. Instead, the sensing layer 64 isspaced apart from the working electrode 58 a, as illustrated in FIG. 4A,and separated from the working electrode 58 a by a separation layer 61.The separation layer 61 typically includes one or more membranes orfilms. In addition to separating the working electrode 58 a from thesensing layer 64, the separation layer 61 may also act as a masstransport limiting layer or an interferent eliminating layer, asdescribed below.

[0133] Typically, a sensing layer 64, which is not in direct contactwith the working electrode 58 a, includes a catalyst that facilitates areaction of the analyte. However, this sensing layer 64 typically doesnot include an electron transfer agent that transfers electrons directlyfrom the working electrode 58 a to the analyte, as the sensing layer 64is spaced apart from the working electrode 58 a. One example of thistype of sensor is a glucose or lactate sensor which includes an enzyme(e.g., glucose oxidase or lactate oxidase, respectively) in the sensinglayer 64. The glucose or lactate reacts with a second compound (e.g.,oxygen) in the presence of the enzyme. The second compound is thenelectrooxidized or electroreduced at the electrode. Changes in thesignal at the electrode indicate changes in the level of the secondcompound in the fluid and are proportional to changes in glucose orlactate level and, thus, correlate to the analyte level.

[0134] In another embodiment, two sensing layers 63, 64 are used, asshown in FIG. 4B. Each of the two sensing layers 63, 64 may beindependently formed on the working electrode 58 a or in proximity tothe working electrode 58 a. One sensing layer 64 is typically, althoughnot necessarily, spaced apart from the working electrode 58 a. Forexample, this sensing layer 64 may include a catalyst which catalyzes areaction of the analyte to form a product compound. The product compoundis then electrolyzed in the second sensing layer 63 which may include anelectron transfer agent to transfer electrons between the workingelectrode 58 a and the product compound and/or a second catalyst tocatalyze a reaction of the product compound to generate a signal at theworking electrode 58 a.

[0135] For example, a glucose or lactate sensor may include a firstsensing layer 64 which is spaced apart from the working electrode andcontains an enzyme, for example, glucose oxidase or lactate oxidase. Thereaction of glucose or lactate in the presence of the appropriate enzymeforms hydrogen peroxide. A second sensing layer 63 is provided directlyon the working electrode 58 a and contains a peroxidase enzyme and anelectron transfer agent to generate a signal at the electrode inresponse to the hydrogen peroxide. The level of hydrogen peroxideindicated by the sensor then correlates to the level of glucose orlactate. Another sensor which operates similarly can be made using asingle sensing layer with both the glucose or lactate oxidase and theperoxidase being deposited in the single sensing layer. Examples of suchsensors are described in U.S. Pat. No. 5,593,852, U.S. patentapplication Ser. No. 08/540,789, and PCT Patent Application No.US98/02403 entitled “Soybean Peroxidase Electrochemical Sensor”, filedon Feb. 11, 1998, Attorney Docket No. M&G 12008.8WOI2, incorporatedherein by reference.

[0136] In some embodiments, one or more of the working electrodes 58 bdo not have a corresponding sensing layer 64, as shown in FIGS. 3A and4A, or have a sensing layer (not shown) which does not contain one ormore components (e.g., an electron transfer agent or catalyst) needed toelectrolyze the analyte. The signal generated at this working electrode58 b typically arises from interferents and other sources, such as ions,in the fluid, and not in response to the analyte (because the analyte isnot electrooxidized or electroreduced). Thus, the signal at this workingelectrode 58 b corresponds to a background signal. The background signalcan be removed from the analyte signal obtained from other workingelectrodes 58 a that are associated with fully-functional sensing layers64 by, for example, subtracting the signal at working electrode 58 bfrom the signal at working electrode 58 a.

[0137] Sensors having multiple working electrodes 58 a may also be usedto obtain more precise results by averaging the signals or measurementsgenerated at these working electrodes 58 a. In addition, multiplereadings at a single working electrode 58 a or at multiple workingelectrodes may be averaged to obtain more precise data.

[0138] Electron Transfer Agent

[0139] In many embodiments, the sensing layer 64 contains one or moreelectron transfer agents in contact with the conductive material 56 ofthe working electrode 58, as shown in FIGS. 3A and 3B. In someembodiments of the invention, there is little or no leaching of theelectron transfer agent away from the working electrode 58 during theperiod in which the sensor 42 is implanted in the patient. A diffusingor leachable (i.e., releasable) electron transfer agent often diffusesinto the analyte-containing fluid, thereby reducing the effectiveness ofthe electrode by reducing the sensitivity of the sensor over time. Inaddition, a diffusing or leaching electron transfer agent in animplantable sensor 42 may also cause damage to the patient. In theseembodiments, preferably, at least 90%, more preferably, at least 95%,and, most preferably, at least 99%, of the electron transfer agentremains disposed on the sensor after immersion in the analyte-containingfluid for 24 hours, and, more preferably, for 72 hours. In particular,for an implantable sensor, preferably, at least 90%, more preferably, atleast 95%, and most preferably, at least 99%, of the electron transferagent remains disposed on the sensor after immersion in the body fluidat 37° C. for 24 hours, and, more preferably, for 72 hours.

[0140] In some embodiments of the invention, to prevent leaching, theelectron transfer agents are bound or otherwise immobilized on theworking electrode 58 or between or within one or more membranes or filmsdisposed over the working electrode 58. The electron transfer agent maybe immobilized on the working electrode 58 using, for example, apolymeric or sol-gel immobilization technique. Alternatively, theelectron transfer agent may be chemically (e.g., ionically, covalently,or coordinatively) bound to the working electrode 58, either directly orindirectly through another molecule, such as a polymer, that is in turnbound to the working electrode 58.

[0141] Application of the sensing layer 64 on a working electrode 58 ais one method for creating a working surface for the working electrode58 a, as shown in FIGS. 3A and 3B. The electron transfer agent mediatesthe transfer of electrons to electrooxidize or electroreduce an analyteand thereby permits a current flow between the working electrode 58 andthe counter electrode 60 via the analyte. The mediation of the electrontransfer agent facilitates the electrochemical analysis of analyteswhich are not suited for direct electrochemical reaction on anelectrode.

[0142] In general, the preferred electron transfer agents areelectroreducible and electrooxidizable ions or molecules having redoxpotentials that are a few hundred millivolts above or below the redoxpotential of the standard calomel electrode (SCE). Preferably, theelectron transfer agents are not more reducing than about −150 mV andnot more oxidizing than about +400 mV versus SCE.

[0143] The electron transfer agent may be organic, organometallic, orinorganic. Examples of organic redox species are quinones and speciesthat in their oxidized state have quinoid structures, such as Nile blueand indophenol. Some quinones and partially oxidized quinhydrones reactwith functional groups of proteins such as the thiol groups of cysteine,the amine groups of lysine and arginine, and the phenolic groups oftyrosine which may render those redox species unsuitable for some of thesensors of the present invention because of the presence of theinterfering proteins in an analyte-containing fluid. Usually substitutedquinones and molecules with quinoid structure are less reactive withproteins and are preferred. A preferred tetrasubstituted quinone usuallyhas carbon atoms in positions 1, 2, 3, and 4.

[0144] In general, electron transfer agents suitable for use in theinvention have structures or charges which prevent or substantiallyreduce the diffusional loss of the electron transfer agent during theperiod of time that the sample is being analyzed. The preferred electrontransfer agents include a redox species bound to a polymer which can inturn be immobilized on the working electrode. The bond between the redoxspecies and the polymer may be covalent, coordinative, or ionic. Usefulelectron transfer agents and methods for producing them are described inU.S. Pat. Nos. 5,264,104; 5,356,786; 5,262,035; and 5,320,725,incorporated herein by reference. Although any organic or organometallicredox species can be bound to a polymer and used as an electron transferagent, the preferred redox species is a transition metal compound orcomplex. The preferred transition metal compounds or complexes includeosmium, ruthenium, iron, and cobalt compounds or complexes. The mostpreferred are osmium compounds and complexes. It will be recognized thatmany of the redox species described below may also be used, typicallywithout a polymeric component, as electron transfer agents in a carrierfluid or in a sensing layer of a sensor where leaching of the electrontransfer agent is acceptable.

[0145] One type of non-releasable polymeric electron transfer agentcontains a redox species covalently bound in a polymeric composition. Anexample of this type of mediator is poly(vinylferrocene).

[0146] Another type of non-releasable electron transfer agent containsan ionically-bound redox species. Typically, this type of mediatorincludes a charged polymer coupled to an oppositely charged redoxspecies. Examples of this type of mediator include a negatively chargedpolymer such as Nafion® (DuPont) coupled to a positively charged redoxspecies such as an osmium or ruthenium polypyridyl cation. Anotherexample of an ionically-bound mediator is a positively charged polymersuch as quaternized poly(4-vinyl pyridine) or poly(1-vinyl imidazole)coupled to a negatively charged redox species such as ferricyanide orferrocyanide. The preferred ionically-bound redox species is a highlycharged redox species bound within an oppositely charged redox polymer.

[0147] In another embodiment of the invention, suitable non-releasableelectron transfer agents include a redox species coordinatively bound toa polymer. For example, the mediator may be formed by coordination of anosmium or cobalt 2,2′-bipyridyl complex to poly(1-vinyl imidazole) orpoly(4-vinyl pyridine).

[0148] The preferred electron transfer agents are osmium transitionmetal complexes with one or more ligands, each ligand having anitrogen-containing heterocycle such as 2,2′-bipyridine,1,10-phenanthroline, or derivatives thereof. Furthermore, the preferredelectron transfer agents also have one or more ligands covalently boundin a polymer, each ligand having at least one nitrogen-containingheterocycle, such as pyridine, imidazole, or derivatives thereof. Thesepreferred electron transfer agents exchange electrons rapidly betweeneach other and the working electrodes 58 so that the complex can berapidly oxidized and reduced.

[0149] One example of a particularly useful electron transfer agentincludes (a) a polymer or copolymer having pyridine or imidazolefunctional groups and (b) osmium cations complexed with two ligands,each ligand containing 2,2′-bipyridine, 1,10-phenanthroline, orderivatives thereof, the two ligands not necessarily being the same.Preferred derivatives of 2,2′-bipyridine for complexation with theosmium cation are 4,4′-dimethyl-2,2′-bipyridine and mono-, di-, andpolyalkoxy-2,2′-bipyridines, such as 4,4′-dimethoxy-2,2′-bipyridine.Preferred derivatives of 1,10-phenanthroline for complexation with theosmium cation are 4,7-dimethyl-1,10-phenanthroline and mono, di-, andpolyalkoxy-1,10-phenanthrolines, such as4,7-dimethoxy-1,10-phenanthroline. Preferred polymers for complexationwith the osmium cation include polymers and copolymers of poly(1-vinylimidazole) (referred to as “PVI”) and poly(4-vinyl pyridine) (referredto as “PVP”). Suitable copolymer substituents of poly(1-vinyl imidazole)include acrylonitrile, acrylamide, and substituted or quaternizedN-vinyl imidazole. Most preferred are electron transfer agents withosmium complexed to a polymer or copolymer of poly(1-vinyl imidazole).

[0150] The preferred electron transfer agents have a redox potentialranging from −100 mV to about +150 mV versus the standard calomelelectrode (SCE). Preferably, the potential of the electron transferagent ranges from −100 mV to +150 mV and more preferably, the potentialranges from −50 mV to +50 mV. The most preferred electron transferagents have osmium redox centers and a redox potential ranging from +50mV to −150 mV versus SCE.

[0151] Catalyst

[0152] The sensing layer 64 may also include a catalyst which is capableof catalyzing a reaction of the analyte. The catalyst may also, in someembodiments, act as an electron transfer agent. One example of asuitable catalyst is an enzyme which catalyzes a reaction of theanalyte. For example, a catalyst, such as a glucose oxidase, glucosedehydrogenase (e.g., pyrroloquinoline quinone glucose dehydrogenase(PQQ)), or oligosaccharide dehydrogenase, may be used when the analyteis glucose. A lactate oxidase or lactate dehydrogenase may be used whenthe analyte is lactate. Laccase may be used when the analyte is oxygenor when oxygen is generated or consumed in response to a reaction of theanalyte.

[0153] Preferably, the catalyst is non-leachably disposed on the sensor,whether the catalyst is part of a solid sensing layer in the sensor orsolvated in a fluid within the sensing layer. More preferably, thecatalyst is immobilized within the sensor (e.g., on the electrode and/orwithin or between a membrane or film) to prevent unwanted leaching ofthe catalyst away from the working electrode 58 and into the patient.This may be accomplished, for example, by attaching the catalyst to apolymer, cross linking the catalyst with another electron transfer agent(which, as described above, can be polymeric), and/or providing one ormore barrier membranes or films with pore sizes smaller than thecatalyst.

[0154] As described above, a second catalyst may also be used. Thissecond catalyst is often used to catalyze a reaction of a productcompound resulting from the catalyzed reaction of the analyte. Thesecond catalyst typically operates with an electron transfer agent toelectrolyze the product compound to generate a signal at the workingelectrode. Alternatively, the second catalyst may be provided in aninterferent-eliminating layer to catalyze reactions that removeinterferents, as described below.

[0155] One embodiment of the invention is an electrochemical sensor inwhich the catalyst is mixed or dispersed in the conductive material 56which forms the conductive trace 52 of a working electrode 58. This maybe accomplished, for example, by mixing a catalyst, such as an enzyme,in a carbon ink and applying the mixture into a channel 54 on thesurface of the substrate 50. Preferably, the catalyst is immobilized inthe channel 53 so that it can not leach away from the working electrode58. This may be accomplished, for example, by curing a binder in thecarbon ink using a curing technique appropriate to the binder. Curingtechniques include, for example, evaporation of a solvent or dispersant,exposure to ultraviolet light, or exposure to heat. Typically, themixture is applied under conditions that do not substantially degradethe catalyst. For example, the catalyst may be an enzyme that isheat-sensitive. The enzyme and conductive material mixture should beapplied and cured, preferably, without sustained periods of heating. Themixture may be cured using evaporation or UV curing techniques or by theexposure to heat that is sufficiently short that the catalyst is notsubstantially degraded.

[0156] Another consideration for in vivo analyte sensors is thethermostability of the catalyst. Many enzymes have only limitedstability at biological temperatures. Thus, it may be necessary to uselarge amounts of the catalyst and/or use a catalyst that is thermostableat the necessary temperature (e.g., 37° C. or higher for normal bodytemperature). A thermostable catalyst may be defined as a catalyst whichloses less than 5% of its activity when held at 37° C. for at least onehour, preferably, at least one day, and more preferably at least threedays. One example of a thermostable catalyst is soybean peroxidase. Thisparticular thermostable catalyst may be used in a glucose or lactatesensor when combined either in the same or separate sensing layers withglucose or lactate oxidase or dehydrogenase. A further description ofthermostable catalysts and their use in electrochemical inventions isfound in U.S. Pat. No. 5,665,222 U.S. patent application Ser. No.08/540,789, and PCT Application No. US98/02403 entitled “SoybeanPeroxidase Electrochemical Sensor”, filed on Feb. 11, 1998, AttorneyDocket No. M&G 12008.8WOI2.

[0157] Electrolysis of the Analyte

[0158] To electrolyze the analyte, a potential (versus a referencepotential) is applied across the working and counter electrodes 58, 60.The minimum magnitude of the applied potential is often dependent on theparticular electron transfer agent, analyte (if the analyte is directlyelectrolyzed at the electrode), or second compound (if a secondcompound, such as oxygen or hydrogen peroxide, whose level is dependenton the analyte level, is directly electrolyzed at the electrode). Theapplied potential usually equals or is more oxidizing or reducing,depending on the desired electrochemical reaction, than the redoxpotential of the electron transfer agent, analyte, or second compound,whichever is directly electrolyzed at the electrode. The potential atthe working electrode is typically large enough to drive theelectrochemical reaction to or near completion.

[0159] The magnitude of the potential may optionally be limited toprevent significant (as determined by the current generated in responseto the analyte) electrochemical reaction of interferents, such as urate,ascorbate, and acetaminophen. The limitation of the potential may beobviated if these interferents have been removed in another way, such asby providing an interferent-limiting barrier, as described below, or byincluding a working electrode 58 b (see FIG. 3A) from which a backgroundsignal may be obtained.

[0160] When a potential is applied between the working electrode 58 andthe counter electrode 60, an electrical current will flow. The currentis a result of the electrolysis of the analyte or a second compoundwhose level is affected by the analyte. In one embodiment, theelectrochemical reaction occurs via an electron transfer agent and theoptional catalyst. Many analytes B are oxidized (or reduced) to productsC by an electron transfer agent species A in the presence of anappropriate catalyst (e.g., an enzyme). The electron transfer agent A isthen oxidized (or reduced) at the electrode. Electrons are collected by(or removed from) the electrode and the resulting current is measured.This process is illustrated by reaction equations (1) and (2) (similarequations may be written for the reduction of the analyte B by a redoxmediator A in the presence of a catalyst):

[0161] As an example, an electrochemical sensor may be based on thereaction of a glucose molecule with two non-leachable ferricyanideanions in the presence of glucose oxidase to produce two non-leachableferrocyanide anions, two hydrogen ions, and gluconolactone. The amountof glucose present is assayed by electrooxidizing the non-leachableferrocyanide anions to non-leachable ferricyanide anions and measuringthe current.

[0162] In another embodiment, a second compound whose level is affectedby the analyte is electrolyzed at the working electrode. In some cases,the analyte D and the second compound, in this case, a reactant compoundE, such as oxygen, react in the presence of the catalyst, as shown inreaction equation (3).

[0163] The reactant compound E is then directly oxidized (or reduced) atthe working electrode, as shown in reaction equation (4)

[0164] Alternatively, the reactant compound E is indirectly oxidized (orreduced) using an electron transfer agent H (optionally in the presenceof a catalyst), that is subsequently reduced or oxidized at theelectrode, as shown in reaction equations (5) and (6).

nH(ox)+E→nH(red)+I  (5) $\begin{matrix}{{n\quad {{H({red})}\overset{electrode}{}n}\quad {H({ox})}} + {ne}^{-}} & (6)\end{matrix}$

[0165] In either case, changes in the concentration of the reactantcompound, as indicated by the signal at the working electrode,correspond inversely to changes in the analyte (i.e., as the level ofanalyte increase then the level of reactant compound and the signal atthe electrode decreases.)

[0166] In other embodiments, the relevant second compound is a productcompound F, as shown in reaction equation (3). The product compound F isformed by the catalyzed reaction of analyte D and then be directlyelectrolyzed at the electrode or indirectly electrolyzed using anelectron transfer agent and, optionally, a catalyst. In theseembodiments, the signal arising from the direct or indirect electrolysisof the product compound F at the working electrode corresponds directlyto the level of the analyte (unless there are other sources of theproduct compound). As the level of analyte increases, the level of theproduct compound and signal at the working electrode increases.

[0167] Those skilled in the art will recognize that there are manydifferent reactions that will achieve the same result; namely theelectrolysis of an analyte or a compound whose level depends on thelevel of the analyte. Reaction equations (1) through (6) illustratenon-limiting examples of such reactions.

[0168] Temperature Probe

[0169] A variety of optional items may be included in the sensor. Oneoptional item is a temperature probe 66 (FIGS. 8 and 11). Thetemperature probe 66 may be made using a variety of known designs andmaterials. One exemplary temperature probe 66 is formed using two probeleads 68, 70 connected to each other through a temperature-dependentelement 72 that is formed using a material with a temperature-dependentcharacteristic. An example of a suitable temperature-dependentcharacteristic is the resistance of the temperature-dependent element72.

[0170] The two probe leads 68, 70 are typically formed using a metal, analloy, a semimetal, such as graphite, a degenerate or highly dopedsemiconductor, or a small-band gap semiconductor. Examples of suitablematerials include gold, silver, ruthenium oxide, titanium nitride,titanium dioxide, indium doped tin oxide, tin doped indium oxide, orgraphite. The temperature-dependent element 72 is typically made using afine trace (e.g., a conductive trace that has a smaller cross-sectionthan that of the probe leads 68, 70) of the same conductive material asthe probe leads, or another material such as a carbon ink, a carbonfiber, or platinum, which has a temperature-dependent characteristic,such as resistance, that provides a temperature-dependent signal when avoltage source is attached to the two probe leads 68, 70 of thetemperature probe 66. The temperature-dependent characteristic of thetemperature-dependent element 72 may either increase or decrease withtemperature. Preferably, the temperature dependence of thecharacteristic of the temperature-dependent element 72 is approximatelylinear with temperature over the expected range of biologicaltemperatures (about 25 to 45° C.), although this is not required.

[0171] Typically, a signal (e.g., a current) having an amplitude orother property that is a function of the temperature can be obtained byproviding a potential across the two probe leads 68, 70 of thetemperature probe 66. As the temperature changes, thetemperature-dependent characteristic of the temperature-dependentelement 72 increases or decreases with a corresponding change in thesignal amplitude. The signal from the temperature probe 66 (e.g., theamount of current flowing through the probe) may be combined with thesignal obtained from the working electrode 58 by, for example, scalingthe temperature probe signal and then adding or subtracting the scaledtemperature probe signal from the signal at the working electrode 58. Inthis manner, the temperature probe 66 can provide a temperatureadjustment for the output from the working electrode 58 to offset thetemperature dependence of the working electrode 58.

[0172] One embodiment of the temperature probe includes probe leads 68,70 formed as two spaced-apart channels with a temperature-dependentelement 72 formed as a cross-channel connecting the two spaced-apartchannels, as illustrated in FIG. 8. The two spaced-apart channelscontain a conductive material, such as a metal, alloy, semimetal,degenerate semiconductor, or metallic compound. The cross-channel maycontain the same material (provided the cross-channel has a smallercross-section than the two spaced-apart channels) as the probe leads 68,70. In other embodiments, the material in the cross-channel is differentthan the material of the probe leads 68, 70.

[0173] One exemplary method for forming this particular temperatureprobe includes forming the two spaced-apart channels and then fillingthem with the metallic or alloyed conductive material. Next, thecross-channel is formed and then filled with the desired material. Thematerial in the cross-channel overlaps with the conductive material ineach of the two spaced-apart channels to form an electrical connection.

[0174] For proper operation of the temperature probe 66, thetemperature-dependent element 72 of the temperature probe 66 can not beshorted by conductive material formed between the two probe leads 68,70. In addition, to prevent conduction between the two probe leads 68,70 by ionic species within the body or sample fluid, a covering may beprovided over the temperature-dependent element 72, and preferably overthe portion of the probe leads 68, 70 that is implanted in the patient.The covering may be, for example, a non-conducting film disposed overthe temperature-dependent element 72 and probe leads 68, 70 to preventthe ionic conduction. Suitable non-conducting films include, forexample, Kapton™ polyimide films (DuPont, Wilmington, Del.).

[0175] Another method for eliminating or reducing conduction by ionicspecies in the body or sample fluid is to use an ac voltage sourceconnected to the probe leads 68, 70. In this way, the positive andnegative ionic species are alternately attracted and repelled duringeach half cycle of the ac voltage. This results in no net attraction ofthe ions in the body or sample fluid to the temperature probe 66. Themaximum amplitude of the ac current through the temperature-dependentelement 72 may then be used to correct the measurements from the workingelectrodes 58.

[0176] The temperature probe can be placed on the same substrate as theelectrodes. Alternatively, a temperature probe may be placed on aseparate substrate. In addition, the temperature probe may be used byitself or in conjunction with other devices.

[0177] Another embodiment of a temperature probe utilizes thetemperature dependence of the conductivity of a solution (e.g., blood orinterstitial fluid). Typically, the conductivity of anelectrolyte-containing solution is dependent on the temperature of thesolution, assuming that the concentration of electrolytes is relativelyconstant. Blood, interstitial fluid, and other bodily fluids aresolutions with relatively constant levels of electrolytes. Thus, asensor 42 can include two or more conductive traces (not shown) whichare spaced apart by a known distance. A portion of these conductivetraces is exposed to the solution and the conductivity between theexposed portions of the conductive traces is measured using knowntechniques (e.g., application of a constant or known current orpotential and measurement of the resulting potential or current,respectively, to determine the conductivity).

[0178] A change in conductivity is related to a change in temperature.This relation can be modeled using linear, quadratic, exponential, orother relations. The parameters for this relationship typically do notvary significantly between most people. The calibration for thetemperature probe can be determined by a variety of methods, including,for example, calibration of each sensor 42 using an independent methodof determining temperature (e.g., a thermometer, an optical orelectrical temperature detector, or the temperature probe 66, describedabove) or calibrating one sensor 42 and using that calibration for allother sensors in a batch based on uniformity in geometry.

[0179] Biocompatible Layer

[0180] An optional film layer 75 is formed over at least that portion ofthe sensor 42 which is subcutaneously inserted into the patient, asshown in FIG. 9. This optional film layer 74 may serve one or morefunctions. The film layer 74 prevents the penetration of largebiomolecules into the electrodes. This is accomplished by using a filmlayer 74 having a pore size that is smaller than the biomolecules thatare to be excluded. Such biomolecules may foul the electrodes and/or thesensing layer 64 thereby reducing the effectiveness of the sensor 42 andaltering the expected signal amplitude for a given analyteconcentration. The fouling of the working electrodes 58 may alsodecrease the effective life of the sensor 42. The biocompatible layer 74may also prevent protein adhesion to the sensor 42, formation of bloodclots, and other undesirable interactions between the sensor 42 andbody.

[0181] For example, the sensor may be completely or partially coated onits exterior with a biocompatible coating. A preferred biocompatiblecoating is a hydrogel which contains at least 20 wt. % fluid when inequilibrium with the analyte-containing fluid. Examples of suitablehydrogels are described in U.S. Pat. No. 5,593,852, incorporated hereinby reference, and include crosslinked polyethylene oxides, such aspolyethylene oxide tetraacrylate.

[0182] Interferent-Eliminating Layer

[0183] An interferent-eliminating layer (not shown) may be included inthe sensor 42. The interferent-eliminating layer may be incorporated inthe biocompatible layer 75 or in the mass transport limiting layer 74(described below) or may be a separate layer. Interferents are moleculesor other species that are electroreduced or electrooxidized at theelectrode, either directly or via an electron transfer agent, to producea false signal. In one embodiment, a film or membrane prevents thepenetration of one or more interferents into the region around theworking electrodes 58. Preferably, this type of interferent-eliminatinglayer is much less permeable to one or more of the interferents than tothe analyte.

[0184] The interferent-eliminating layer may include ionic components,such as Nafion®, incorporated into a polymeric matrix to reduce thepermeability of the interferent-eliminating layer to ionic interferentshaving the same charge as the ionic components. For example, negativelycharged compounds or compounds that form negative ions may beincorporated in the interferent-eliminating layer to reduce thepermeation of negative species in the body or sample fluid.

[0185] Another example of an interferent-eliminating layer includes acatalyst for catalyzing a reaction which removes interferents. Oneexample of such a catalyst is a peroxidase. Hydrogen peroxide reactswith interferents, such as acetaminophen, urate, and ascorbate. Thehydrogen peroxide may be added to the analyte-containing fluid or may begenerated in situ, by, for example, the reaction of glucose or lactatein the presence of glucose oxidase or lactate oxidase, respectively.Examples of interferent eliminating layers include a peroxidase enzymecrosslinked (a) using gluteraldehyde as a crosslinking agent or (b)oxidation of oligosaccharide groups in the peroxidase glycoenzyme withNaIO₄, followed by coupling of the aldehydes formed to hydrazide groupsin a polyacrylamide matrix to form hydrazones are describe in U.S. Pat.Nos. 5,262,305 and 5,356,786, incorporated herein by reference.

[0186] Mass Transport Limiting Layer

[0187] A mass transport limiting layer 74 may be included with thesensor to act as a diffusion-limiting barrier to reduce the rate of masstransport of the analyte, for example, glucose or lactate, into theregion around the working electrodes 58. By limiting the diffusion ofthe analyte, the steady state concentration of the analyte in theproximity of the working electrode 58 (which is proportional to theconcentration of the analyte in the body or sample fluid) can bereduced. This extends the upper range of analyte concentrations that canstill be accurately measured and may also expand the range in which thecurrent increases approximately linearly with the level of the analyte.

[0188] It is preferred that the permeability of the analyte through thefilm layer 74 vary little or not at all with temperature, so as toreduce or eliminate the variation of current with temperature. For thisreason, it is preferred that in the biologically relevant temperaturerange from about 25° C. to about 45° C., and most importantly from 30°C. to 40° C., neither the size of the pores in the film nor itshydration or swelling change excessively. Preferably, the mass transportlimiting layer is made using a film that absorbs less than 5 wt. % offluid over 24 hours. This may reduce or obviate any need for atemperature probe. For implantable sensors, it is preferable that themass transport limiting layer is made using a film that absorbs lessthan 5 wt. % of fluid over 24 hours at 37° C.

[0189] Particularly useful materials for the film layer 74 are membranesthat do not swell in the analyte-containing fluid that the sensor tests.Suitable membranes include 3 to 20,000 nm diameter pores. Membraneshaving 5 to 500 nm diameter pores with well-defined, uniform pore sizesand high aspect ratios are preferred. In one embodiment, the aspectratio of the pores is preferably two or greater and more preferably fiveor greater.

[0190] Well-defined and uniform pores can be made by track etching apolymeric membrane using accelerated electrons, ions, or particlesemitted by radioactive nuclei. Most preferred are anisotropic,polymeric, track etched membranes that expand less in the directionperpendicular to the pores than in the direction of the pores whenheated. Suitable polymeric membranes included polycarbonate membranesfrom Poretics (Livermore, Calif., catalog number 19401, 0.01 μm poresize polycarbonate membrane) and Corning Costar Corp. (Cambridge, Mass.,Nucleopore™ brand membranes with 0.015 μm pore size). Other polyolefinand polyester films may be used. It is preferred that the permeabilityof the mass transport limiting membrane changes no more than 4%,preferably, no more than 3%, and, more preferably, no more than 2%, per° C. in the range from 30° C. to 40° C. when the membranes resides inthe subcutaneous interstitial fluid.

[0191] In some embodiments of the invention, the mass transport limitinglayer 74 may also limit the flow of oxygen into the sensor 42. This canimprove the stability of sensors 42 that are used in situations wherevariation in the partial pressure of oxygen causes non-linearity insensor response. In these embodiments, the mass transport limiting layer74 restricts oxygen transport by at least 40%, preferably at least 60%,and more preferably at least 80%, than the membrane restricts transportof the analyte. For a given type of polymer, films having a greaterdensity (e.g., a density closer to that of the crystalline polymer) arepreferred. Polyesters, such as polyethylene terephthalate, are typicallyless permeable to oxygen and are, therefore, preferred overpolycarbonate membranes.

[0192] Anticlotting Agent

[0193] An implantable sensor may also, optionally, have an anticlottingagent disposed on a portion the substrate which is implanted into apatient. This anticlotting agent may reduce or eliminate the clotting ofblood or other body fluid around the sensor, particularly afterinsertion of the sensor. Blood clots may foul the sensor orirreproducibly reduce the amount of analyte which diffuses into thesensor. Examples of useful anticlotting agents include heparin andtissue plasminogen activator (TPA), as well as other known anticlottingagents.

[0194] The anticlotting agent may be applied to at least a portion ofthat part of the sensor 42 that is to be implanted. The anticlottingagent may be applied, for example, by bath, spraying, brushing, ordipping. The anticlotting agent is allowed to dry on the sensor 42. Theanticlotting agent may be immobilized on the surface of the sensor or itmay be allowed to diffuse away from the sensor surface. Typically, thequantities of anticlotting agent disposed on the sensor are far belowthe amounts typically used for treatment of medical conditions involvingblood clots and, therefore, have only a limited, localized effect.

[0195] Sensor Lifetime

[0196] The sensor 42 may be designed to be a replaceable component in anin vivo analyte monitor, and particularly in an implantable analytemonitor. Typically, the sensor 42 is capable of operation over a periodof days. Preferably, the period of operation is at least one day, morepreferably at least three days, and most preferably at least one week.The sensor 42 can then be removed and replaced with a new sensor. Thelifetime of the sensor 42 may be reduced by the fouling of theelectrodes or by the leaching of the electron transfer agent orcatalyst. These limitations on the longevity of the sensor 42 can beovercome by the use of a biocompatible layer 75 or non-leachableelectron transfer agent and catalyst, respectively, as described above.

[0197] Another primary limitation on the lifetime of the sensor 42 isthe temperature stability of the catalyst. Many catalysts are enzymes,which are very sensitive to the ambient temperature and may degrade attemperatures of the patient's body (e.g., approximately 37° C. for thehuman body). Thus, robust enzymes should be used where available. Thesensor 42 should be replaced when a sufficient amount of the enzyme hasbeen deactivated to introduce an unacceptable amount of error in themeasurements.

[0198] Insertion Device

[0199] An insertion device 120 can be used to subcutaneously insert thesensor 42 into the patient, as illustrated in FIG. 12. The insertiondevice 120 is typically formed using structurally rigid materials, suchas metal or rigid plastic. Preferred materials include stainless steeland ABS (acrylonitrile-butadiene-styrene) plastic. In some embodiments,the insertion device 120 is pointed and/or sharp at the tip 121 tofacilitate penetration of the skin of the patient. A sharp, thininsertion device may reduce pain felt by the patient upon insertion ofthe sensor 42. In other embodiments, the tip 121 of the insertion device120 has other shapes, including a blunt or flat shape. These embodimentsmay be particularly useful when the insertion device 120 does notpenetrate the skin but rather serves as a structural support for thesensor 42 as the sensor 42 is pushed into the skin.

[0200] The insertion device 120 may have a variety of cross-sectionalshapes, as shown in FIGS. 13A, 13B, and 13C. The insertion device 120illustrated in FIG. 13A is a flat, planar, pointed strip of rigidmaterial which may be attached or otherwise coupled to the sensor 42 toease insertion of the sensor 42 into the skin of the patient, as well asto provide structural support to the sensor 42 during insertion. Theinsertion devices 120 of FIGS. 13B and 13C are U- or V-shaped implementsthat support the sensor 42 to limit the amount that the sensor 42 maybend or bow during insertion. The cross-sectional width 124 of theinsertion devices 120 illustrated in FIGS. 13B and 13C is typically 1 mmor less, preferably 700 μm or less, more preferably 500 μm or less, andmost preferably 300 μm or less. The cross-sectional height 126 of theinsertion device 120 illustrated in FIGS. 13B and 13C is typically about1 mm or less, preferably about 700 μm or less, and more preferably about500 μm or less.

[0201] The sensor 42 itself may include optional features to facilitateinsertion. For example, the sensor 42 may be pointed at the tip 123 toease insertion, as illustrated in FIG. 12. In addition, the sensor 42may include a barb 125 which helps retain the sensor 42 in thesubcutaneous tissue of the patient. The barb 125 may also assist inanchoring the sensor 42 within the subcutaneous tissue of the patientduring operation of the sensor 42. However, the barb 125 is typicallysmall enough that little damage is caused to the subcutaneous tissuewhen the sensor 42 is removed for replacement. The sensor 42 may alsoinclude a notch 127 that can be used in cooperation with a correspondingstructure (not shown) in the insertion device to apply pressure againstthe sensor 42 during insertion, but disengage as the insertion device120 is removed. One example of such a structure in the insertion deviceis a rod (not shown) between two opposing sides of an insertion device120 and at an appropriate height of the insertion device 120.

[0202] In operation, the sensor 42 is placed within or next to theinsertion device 120 and then a force is provided against the insertiondevice 120 and/or sensor 42 to carry the sensor 42 into the skin of thepatient. In one embodiment, the force is applied to the sensor 42 topush the sensor into the skin, while the insertion device 120 remainsstationary and provides structural support to the sensor 42.Alternatively, the force is applied to the insertion device 120 andoptionally to the sensor 42 to push a portion of both the sensor 42 andthe insertion device 120 through the skin of the patient and into thesubcutaneous tissue. The insertion device 120 is optionally pulled outof the skin and subcutaneous tissue with the sensor 42 remaining in thesubcutaneous tissue due to frictional forces between the sensor 42 andthe patient's tissue. If the sensor 42 includes the optional barb 125,then this structure may also facilitate the retention of the sensor 42within the interstitial tissue as the barb catches in the tissue.

[0203] The force applied to the insertion device 120 and/or the sensor42 may be applied manually or mechanically. Preferably, the sensor 42 isreproducibly inserted through the skin of the patient. In oneembodiment, an insertion gun is used to insert the sensor. One exampleof an insertion gun 200 for inserting a sensor 42 is shown in FIG. 26.The insertion gun 200 includes a housing 202 and a carrier 204. Theinsertion device 120 is typically mounted on the carrier 204 and thesensor 42 is pre-loaded into the insertion device 120. The carrier 204drives the sensor 42 and, optionally, the insertion device 120 into theskin of the patient using, for example, a cocked or wound spring, aburst of compressed gas, an electromagnet repelled by a second magnet,or the like, within the insertion gun 200. In some instances, forexample, when using a spring, the carrier 204 and insertion device maybe moved, cocked, or otherwise prepared to be directed towards the skinof the patient.

[0204] After the sensor 42 is inserted, the insertion gun 200 maycontain a mechanism which pulls the insertion device 120 out of the skinof the patient. Such a mechanism may use a spring, electromagnet, or thelike to remove the insertion device 120.

[0205] The insertion gun may be reusable. The insertion device 120 isoften disposable to avoid the possibility of contamination.Alternatively, the insertion device 120 may be sterilized and reused. Inaddition, the insertion device 120 and/or the sensor 42 may be coatedwith an anticlotting agent to prevent fouling of the sensor 42.

[0206] In one embodiment, the sensor 42 is injected between 2 to 12 mminto the interstitial tissue of the patient for subcutaneousimplantation. Preferably, the sensor is injected 3 to 9 mm, and morepreferably 5 to 7 mm, into the interstitial tissue. Other embodiments ofthe invention, may include sensors implanted in other portions of thepatient, including, for example, in an artery, vein, or organ. The depthof implantation varies depending on the desired implantation target.

[0207] Although the sensor 42 may be inserted anywhere in the body, itis often desirable that the insertion site be positioned so that theon-skin sensor control unit 44 can be concealed. In addition, it isoften desirable that the insertion site be at a place on the body with alow density of nerve endings to reduce the pain to the patient. Examplesof preferred sites for insertion of the sensor 42 and positioning of theon-skin sensor control unit 44 include the abdomen, thigh, leg, upperarm, and shoulder.

[0208] An insertion angle is measured from the plane of the skin (i.e.,inserting the sensor perpendicular to the skin would be a 90° insertionangle). Insertion angles usually range from 10 to 90°, typically from 15to 60°, and often from 30 to 45°.

[0209] On-Skin Sensor Control Unit

[0210] The on-skin sensor control unit 44 is configured to be placed onthe skin of a patient. The on-skin sensor control unit 44 is optionallyformed in a shape that is comfortable to the patient and which maypermit concealment, for example, under a patient's clothing. The thigh,leg, upper arm, shoulder, or abdomen are convenient parts of thepatient's body for placement of the on-skin sensor control unit 44 tomaintain concealment. However, the on-skin sensor control unit 44 may bepositioned on other portions of the patient's body. One embodiment ofthe on-skin sensor control unit 44 has a thin, oval shape to enhanceconcealment, as illustrated in FIGS. 14-16. However, other shapes andsizes may be used.

[0211] The particular profile, as well as the height, width, length,weight, and volume of the on-skin sensor control unit 44 may vary anddepends, at least in part, on the components and associated functionsincluded in the on-skin sensor control unit 44, as discussed below. Forexample, in some embodiments, the on-skin sensor control unit 44 has aheight of 1.3 cm or less, and preferably 0.7 cm or less. In someembodiments, the on-skin sensor control unit 44 has a weight of 90 gramsor less, preferably 45 grams or less, and more preferably 25 grams orless. In some embodiments, the on-skin sensor control unit 44 has avolume of about 15 cm³ or less, preferably about 10 cm³ or less, morepreferably about 5 cm³ or less, and most preferably about 2.5 cm³ orless.

[0212] The on-skin sensor control unit 44 includes a housing 45, asillustrated in FIGS. 14-16. The housing 45 is typically formed as asingle integral unit that rests on the skin of the patient. The housing45 typically contains most or all of the electronic components,described below, of the on-skin sensor control unit 44. The on-skinsensor control unit 44 usually includes no additional cables or wires toother electronic components or other devices. If the housing includestwo or more parts, then those parts typically fit together to form asingle integral unit.

[0213] The housing 45 of the on-skin sensor control unit 44, illustratedin FIGS. 14-16, may be formed using a variety of materials, including,for example, plastic and polymeric materials, particularly rigidthermoplastics and engineering thermoplastics. Suitable materialsinclude, for example, polyvinyl chloride, polyethylene, polypropylene,polystyrene, ABS polymers, and copolymers thereof. The housing 45 of theon-skin sensor control unit 44 may be formed using a variety oftechniques including, for example, injection molding, compressionmolding, casting, and other molding methods. Hollow or recessed regionsmay be formed in the housing 45 of the on-skin sensor control unit 44.The electronic components of the on-skin sensor control unit 44,described below, and/or other items, such as a battery or a speaker foran audible alarm, may be placed in the hollow or recessed areas.

[0214] In some embodiments, conductive contacts 80 are provided on theexterior of the housing 45. In other embodiments, the conductivecontacts 80 are provided on the interior of the housing 45, for example,within a hollow or recessed region.

[0215] In some embodiments, the electronic components and/or other itemsare incorporated into the housing 45 of the on-skin sensor control unit44 as the plastic or polymeric material is molded or otherwise formed.In other embodiments, the electronic components and/or other items areincorporated into the housing 45 as the molded material is cooling orafter the molded material has been reheated to make it pliable.Alternatively, the electronic components and/or other items may besecured to the housing 45 using fasteners, such as screws, nuts andbolts, nails, staples, rivets, and the like or adhesives, such ascontact adhesives, pressure sensitive adhesives, glues, epoxies,adhesive resins, and the like. In some cases, the electronic componentsand/or other items are not affixed to the housing 45 at all.

[0216] In some embodiments, the housing 45 of the on-skin sensor controlunit 44 is a single piece. The conductive contacts 80 may be formed onthe exterior of the housing 45 or on the interior of the housing 45provided there is a port 78 in the housing 45 through which the sensor42 can be directed to access the conductive contacts 80.

[0217] In other embodiments, the housing 45 of the on-skin sensorcontrol unit 44 is formed in at least two separate portions that fittogether to form the housing 45, for example, a base 74 and a cover 76,as illustrated in FIGS. 14-16. The two or more portions of the housing45 may be entirely separate from each other. Alternatively, at leastsome of the two or more portions of the housing 45 may be connectedtogether, for example, by a hinge, to facilitate the coupling of theportions to form the housing 45 of the on-skin sensor control unit 44.

[0218] These two or more separate portions of the housing 45 of theon-skin sensor control unit 44 may have complementary, interlockingstructures, such as, for example, interlocking ridges or a ridge on onecomponent and a complementary groove on another component, so that thetwo or more separate components may be easily and/or firmly coupledtogether. This may be useful, particularly if the components are takenapart and fit together occasionally, for example, when a battery orsensor 42 is replaced. However, other fasteners may also be used tocouple the two or more components together, including, for example,screws, nuts and bolts, nails, staples, rivets, or the like. Inaddition, adhesives, both permanent or temporary, may be used including,for example, contact adhesives, pressure sensitive adhesives, glues,epoxies, adhesive resins, and the like.

[0219] Typically, the housing 45 is at least water resistant to preventthe flow of fluids into contact with the components in the housing,including, for example, the conductive contacts 80. Preferably, thehousing is waterproof. In one embodiment, two or more components of thehousing 45, for example, the base 74 and the cover 76, fit togethertightly to form a hermetic, waterproof, or water resistant seal so thatfluids can not flow into the interior of the on-skin sensor control unit44. This may be useful to avoid corrosion currents and/or degradation ofitems within the on-skin sensor control unit 44, such as the conductivecontacts, the battery, or the electronic components, particularly whenthe patient engages in such activities as showering, bathing, orswimming.

[0220] Water resistant, as used herein, means that there is nopenetration of water through a water resistant seal or housing whenimmersed in water at a depth of one meter at sea level. Waterproof, asused herein, means that there is no penetration of water through thewaterproof seal or housing when immersed in water at a depth of tenmeters, and preferably fifty meters, at sea level. It is often desirablethat the electronic circuitry, power supply (e.g., battery), andconductive contacts of the on-skin sensor control unit, as well as thecontact pads of the sensor, are contained in a water resistant, andpreferably, a waterproof, environment.

[0221] In addition to the portions of the housing 45, such as the base74 and cover 76, there may be other individually-formed pieces of theon-skin sensor control unit 44, which may be assembled during or aftermanufacture. One example of an individually-formed piece is a cover forelectronic components that fits a recess in the base 74 or cover 76.Another example is a cover for a battery provided in the base 74 orcover 76. These individually-formed pieces of the on-skin sensor controlunit 44 may be permanently affixed, such as, for example, a cover forelectronic components, or removably affixed, such as, for example, aremovable cover for a battery, to the base 74, cover 76, or othercomponent of the on-skin sensor control unit 44. Methods for affixingthese individually-formed pieces include the use of fasteners, such asscrews, nuts and bolts, staples, nails, rivets, and the like, frictionalfasteners, such as tongue and groove structures, and adhesives, such ascontact adhesives, pressure sensitive adhesives, glues, epoxies,adhesive resins, and the like.

[0222] One embodiment of the on-skin sensor control unit 44 is adisposable unit complete with a battery for operating the unit. Thereare no portions of the unit that the patient needs to open or remove,thereby reducing the size of the unit and simplifying its construction.The on-skin sensor control unit 44 optionally remains in a sleep modeprior to use to conserve the battery's power. The on-skin sensor controlunit 44 detects that it is being used and activates itself. Detection ofuse may be through a number of mechanisms. These include, for example,detection of a change in resistance across the electrical contacts,actuation of a switch upon mating the on-skin sensor control unit 44with a mounting unit 77 (see FIGS. 27A and 28A). The on-skin sensorcontrol unit 44 is typically replaced when it no longer operates withinthreshold limits, for example, if the battery or other power source doesnot generate sufficient power. Often this embodiment of the on-skinsensor control unit 44 has conductive contacts 80 on the exterior of thehousing 45. Once the sensor 42 is implanted in the patient, the sensorcontrol unit 44 is placed over the sensor 42 with the conductivecontacts 80 in contact with the contact pads 49 of the sensor 42.

[0223] The on-skin sensor control unit 44 is typically attached to theskin 75 of the patient, as illustrated in FIG. 17. The on-skin sensorcontrol unit 44 may be attached by a variety of techniques including,for example, by adhering the on-skin sensor control unit 44 directly tothe skin 75 of the patient with an adhesive provided on at least aportion of the housing 45 of the on-skin sensor control unit 44 whichcontacts the skin 75 or by suturing the on-skin sensor control unit 44to the skin 75 through suture openings (not shown) in the sensor controlunit 44.

[0224] Another method of attaching the housing 45 of the on-skin sensorcontrol unit 44 to the skin 75 includes using a mounting unit, 77. Themounting unit 77 is often a part of the on-skin sensor control unit 44.One example of a suitable mounting unit 77 is a double-sided adhesivestrip, one side of which is adhered to a surface of the skin of thepatient and the other side is adhered to the on-skin sensor control unit44. In this embodiment, the mounting unit 77 may have an optionalopening 79 which is large enough to allow insertion of the sensor 42through the opening 79. Alternatively, the sensor may be insertedthrough a thin adhesive and into the skin.

[0225] A variety of adhesives may be used to adhere the on-skin sensorcontrol unit 44 to the skin 75 of the patient, either directly or usingthe mounting unit 77, including, for example, pressure sensitiveadhesives (PSA) or contact adhesives. Preferably, an adhesive is chosenwhich is not irritating to all or a majority of patients for at leastthe period of time that a particular sensor 42 is implanted in thepatient. Alternatively, a second adhesive or other skin-protectingcompound may be included with the mounting unit so that a patient, whoseskin is irritated by the adhesive on the mounting unit 77, can cover hisskin with the second adhesive or other skin-protecting compound and thenplace the mounting unit 77 over the second adhesive or otherskin-protecting compound. This should substantially prevent theirritation of the skin of the patient because the adhesive on themounting unit 77 is no longer in contact with the skin, but is insteadin contact with the second adhesive or other skin-protecting compound.

[0226] When the sensor 42 is changed, the on-skin sensor control unit 44may be moved to a different position on the skin 75 of the patient, forexample, to avoid excessive irritation. Alternatively, the on-skinsensor control unit 44 may remain at the same place on the skin of thepatient until it is determined that the unit 44 should be moved.

[0227] Another embodiment of a mounting unit 77 used in an on-skinsensor control unit 44 is illustrated in FIGS. 27A and 27B. The mountingunit 77 and a housing 45 of an on-skin sensor control unit 44 aremounted together in, for example, an interlocking manner, as shown inFIG. 27A. The mounting unit 77 is formed, for example, using plastic orpolymer materials, including, for example, polyvinyl chloride,polyethylene, polypropylene, polystyrene, ABS polymers, and copolymersthereof. The mounting unit 77 may be formed using a variety oftechniques including, for example, injection molding, compressionmolding, casting, and other molding methods.

[0228] The mounting unit 77 typically includes an adhesive on a bottomsurface of the mounting unit 77 to adhere to the skin of the patient orthe mounting unit 77 is used in conjunction with, for example,double-sided adhesive tape or the like. The mounting unit 77 typicallyincludes an opening 79 through which the sensor 42 is inserted, as shownin FIG. 27B. The mounting unit 77 may also include a support structure220 for holding the sensor 42 in place and against the conductivecontacts 80 on the on-skin sensor control unit 42. The mounting unit 77,also, optionally, includes a positioning structure 222, such as anextension of material from the mounting unit 77, that corresponds to astructure (not shown), such as an opening, on the sensor 42 tofacilitate proper positioning of the sensor 42, for example, by aligningthe two complementary structures.

[0229] In another embodiment, a coupled mounting unit 77 and housing 45of an on-skin sensor control unit 44 is provided on an adhesive patch204 with an optional cover 206 to protect and/or confine the housing 45of the on-skin sensor control unit 44, as illustrated in FIG. 28A. Theoptional cover may contain an adhesive or other mechanism for attachmentto the housing 45 and/or mounting unit 77. The mounting unit 77typically includes an opening 49 through which a sensor 42 is disposed,as shown in FIG. 28B. The opening 49 may optionally be configured toallow insertion of the sensor 42 through the opening 49 using aninsertion device 120 or insertion gun 200 (see FIG. 26). The housing 45of the on-skin sensor control unit 44 has a base 74 and a cover 76, asillustrated in FIG. 28C. A bottom view of the housing 45, as shown inFIG. 28D, illustrates ports 230 through which conductive contacts (notshown) extend to connect with contact pads on the sensor 42. A board 232for attachment of circuit components may optionally be provided withinthe on-skin sensor control unit 44, as illustrated in FIG. 28E.

[0230] In some embodiments, the adhesive on the on-skin sensor controlunit 44 and/or on any of the embodiments of the mounting unit 77 iswater resistant or waterproof to permit activities such as showeringand/or bathing while maintaining adherence of the on-skin sensor controlunit 44 to the skin 75 of the patient and, at least in some embodiments,preventing water from penetrating into the sensor control unit 44. Theuse of a water resistant or waterproof adhesive combined with a waterresistant or waterproof housing 45 protects the components in the sensorcontrol unit 44 and the contact between the conductive contacts 80 andthe sensor 42 from damage or corrosion. An example of a non-irritatingadhesive that repels water is Tegaderm (3M, St. Paul, Minn.).

[0231] In one embodiment, the on-skin sensor control unit 44 includes asensor port 78 through which the sensor 42 enters the subcutaneoustissue of the patient, as shown in FIGS. 14 to 16. The sensor 42 may beinserted into the subcutaneous tissue of the patient through the sensorport 78. The on-skin sensor control unit 44 may then be placed on theskin of the patient with the sensor 42 being threaded through the sensorport 78. If the housing 45 of the sensor 42 has, for example, a base 74and a cover 76, then the cover 76 may be removed to allow the patient toguide the sensor 42 into the proper position for contact with theconductive contacts 80.

[0232] Alternatively, if the conductive contacts 80 are within thehousing 45 the patient may slide the sensor 42 into the housing 45 untilcontact is made between the contact pads 49 and the conductive contacts80. The sensor control unit 44 may have a structure which obstructs thesliding of the sensor 42 further into the housing once the sensor 42 isproperly positioned with the contact pads 49 in contact with theconductive contacts 80.

[0233] In other embodiments, the conductive contacts 80 are on theexterior of the housing 45 (see e.g., FIGS. 27A-27B and 28A-28E). Inthese embodiments, the patient guides the contacts pads 49 of the sensor42 into contact with the conductive contacts 80. In some cases, aguiding structure may be provided on the housing 45 which guides thesensor 42 into the proper position. An example of such a structureincludes a set of guiding rails extending from the housing 45 and havingthe shape of the sensor 42.

[0234] In some embodiments, when the sensor 42 is inserted using aninsertion device 120 (see FIG. 12), the tip of the insertion device 120or optional insertion gun 200 (see FIG. 26) is positioned against theskin or the mounting unit 77 at the desired insertion point. In someembodiments, the insertion device 120 is positioned on the skin withoutany guide. In other embodiments, the insertion device 120 or insertiongun 200 is positioned using guides (not shown) in the mounting unit 77or other portion of the on-skin sensor control unit 44. In someembodiments, the guides, opening 79 in the mounting unit 77 and/orsensor port 78 in the housing 45 of the on-skin sensor control unit 44have a shape which is complementary to the shape of the tip of theinsertion device 120 and/or insertion gun 200 to limit the orientationof the insertion device 120 and/or insertion gun 200 relative to theopening 79 and/or sensor port 78. The sensor can then be subcutaneouslyinserted into the patient by matching the complementary shape of theopening 79 or sensor port 78 with the insertion device 120 and/orinsertion gun 200.

[0235] In some embodiments, the shapes of a) the guides, opening 79, orsensor port 78, and (b) the insertion device 120 or insertion gun 200are configured such that the two shapes can only be matched in a singleorientation. This aids in inserting the sensor 42 in the sameorientation each time a new sensor is inserted into the patient. Thisuniformity in insertion orientation may be required in some embodimentsto ensure that the contact pads 49 on the sensor 42 are correctlyaligned with appropriate conductive contacts 80 on the on-skin sensorcontrol unit 44. In addition, the use of the insertion gun, as describedabove, may ensure that the sensor 42 is inserted at a uniform,reproducible depth.

[0236] The sensor 42 and the electronic components within the on-skinsensor control unit 44 are coupled via conductive contacts 80, as shownin FIGS. 14-16. The one or more working electrodes 58, counter electrode60 (or counter/reference electrode), optional reference electrode 62,and optional temperature probe 66 are attached to individual conductivecontacts 80. In the illustrated embodiment of FIGS. 14-16, theconductive contacts 80 are provided on the interior of the on-skinsensor control unit 44. Other embodiments of the on-skin sensor controlunit 44 have the conductive contacts disposed on the exterior of thehousing 45. The placement of the conductive contacts 80 is such thatthey are in contact with the contact pads 49 on the sensor 42 when thesensor 42 is properly positioned within the on-skin sensor control unit44.

[0237] In the illustrated embodiment of FIGS. 14-16, the base 74 andcover 76 of the on-skin sensor control unit 44 are formed such that,when the sensor 42 is within the on-skin sensor control unit 44 and thebase 74 and cover 76 are fitted together, the sensor 42 is bent. In thismanner, the contact pads 49 on the sensor 42 are brought into contactwith the conductive contacts 80 of the on-skin sensor control unit 44.The on-skin sensor control unit 44 may optionally contain a supportstructure 82 to hold, support, and/or guide the sensor 42 into thecorrect position.

[0238] Non-limiting examples of suitable conductive contacts 80 areillustrated in FIGS. 19A-19D. In one embodiment, the conductive contacts80 are pins 84 or the like, as illustrated in FIG. 19A, which arebrought into contact with the contact pads 49 on the sensor 42 when thecomponents of the on-skin sensor control unit 44, for example, the base74 and cover 76, are fitted together. A support 82 may be provided underthe sensor 42 to promote adequate contact between the contact pads 49 onthe sensor 42 and the pins 84. The pins are typically made using aconductive material, such as a metal or alloy, for example, copper,stainless steel, or silver. Each pin has a distal end that extends fromthe on-skin sensor control unit 44 for contacting the contact pads 49 onthe sensor 42. Each pin 84 also has a proximal end that is coupled to awire or other conductive strip that is, in turn, coupled to the rest ofthe electronic components (e.g., the voltage source 95 and measurementcircuit 96 of FIGS. 18A and 18B) within the on-skin sensor control unit44. Alternatively, the pins 84 may be coupled directly to the rest ofthe electronics.

[0239] In another embodiment, the conductive contacts 80 are formed as aseries of conducting regions 88 with interspersed insulating regions 90,as illustrated in FIG. 19B. The conducting regions 88 may be as large orlarger than the contact pads 49 on the sensor 42 to alleviateregistration concerns. However, the insulating regions 90 should havesufficient width so that a single conductive region 88 does not overlapwith two contact pads 49 as determined based on the expected variationin the position of the sensor 42 and contact pads 49 with respect to theconductive contacts 80. The conducting regions 88 are formed usingmaterials such as metals, alloys, or conductive carbon. The insulatingregions 90 may be formed using known insulating materials including, forexample, insulating plastic or polymer materials.

[0240] In a further embodiment, a unidirectional conducting adhesive 92may be used between the contact pads 49 on the sensor 42 and conductivecontacts 80 implanted or otherwise formed in the on-skin sensor controlunit 44, as shown in FIG. 19C.

[0241] In yet another embodiment, the conductive contacts 80 areconductive members 94 that extend from a surface of the on-skin sensorcontrol unit 44 to contact the contact pads 49, as shown in FIG. 19D. Avariety of different shapes may be used for these members, however, theyshould be electrically insulated from each other. The conductive members94 may be made using metal, alloy, conductive carbon, or conductingplastics and polymers.

[0242] Any of the exemplary conductive contacts 80 described above mayextend from either the upper surface of the interior of the on-skinsensor control unit 44, as illustrated in FIGS. 19A-19C, or from thelower surface of the interior of the on-skin sensor control unit 44, asillustrated in FIG. 19D, or from both the upper and lower surfaces ofthe interior of the on-skin sensor control unit 44, particularly whenthe sensor 42 has contact pads 49 on both sides of the sensor.

[0243] Conductive contacts 80 on the exterior of the housing 45 may alsohave a variety of shapes as indicated in FIGS. 19E and 19F. For example,the conductive contacts 80 may be embedded in (FIG. 19E) or extendingout of (FIG. 19F) the housing 45.

[0244] The conductive contacts 80 are preferably made using a materialwhich will not corrode due to contact with the contact pads 49 of thesensor 42. Corrosion may occur when two different metals are brought incontact. Thus, if the contact pads 49 are formed using carbon then thepreferred conductive contacts 80 may be made using any material,including metals or alloys. However, if any of the contact pads 49 aremade with a metal or alloy then the preferred conductive contacts 80 forcoupling with the metallic contact pads are made using a non-metallicconductive material, such as conductive carbon or a conductive polymer,or the conductive contacts 80 and the contact pads 49 are separated by anon-metallic material, such as a unidirectional conductive adhesive.

[0245] In one embodiment, electrical contacts are eliminated between thesensor 42 and the on-skin sensor control unit 44. Power is transmittedto the sensor via inductive coupling, using, for example, closely spaceantennas (e.g., facing coils) (not shown) on the sensor and the on-skinsensor control unit. Changes in the electrical characteristics of thesensor control unit 44 (e.g., current) induce a changing magnetic fieldin the proximity of the antenna. The changing magnetic field induces acurrent in the antenna of the sensor. The close proximity of the sensorand on-skin sensor control unit results in reasonably efficient powertransmission. The induced current in the sensor may be used to powerpotentiostats, operational amplifiers, capacitors, integrated circuits,transmitters, and other electronic components built into the sensorstructure. Data is transmitted back to the sensor control unit, using,for example, inductive coupling via the same or different antennasand/or transmission of the signal via a transmitter on the sensor. Theuse of inductive coupling can eliminate electrical contacts between thesensor and the on-skin sensor control unit. Such contacts are commonly asource of noise and failure. Moreover, the sensor control unit may thenbe entirely sealed which may increase the waterproofing of the on-skinsensor control unit.

[0246] An exemplary on-skin sensor control unit 44 can be prepared andused in the following manner. A mounting unit 77 having adhesive on thebottom is applied to the skin. An insertion gun 200 (see FIG. 26)carrying the sensor 42 and the insertion device 120 is positionedagainst the mounting unit 77. The insertion gun 200 and mounting unit 77are optionally designed such that there is only one position in whichthe two properly mate. The insertion gun 200 is activated and a portionof the sensor 42 and optionally a portion of the insertion device 120are driven through the skin into, for example, the subcutaneous tissue.The insertion gun 200 withdraws the insertion device 200, leaving theportion of the sensor 42 inserted through the skin. The housing 45 ofthe on-skin control unit 44 is then coupled to the mounting unit 77.Optionally, the housing 45 and the mounting unit 77 are formed such thatthere is only one position in which the two properly mate. The mating ofthe housing 45 and the mounting unit 77 establishes contact between thecontact pads 49 (see e.g., FIG. 2) on the sensor 42 and the conductivecontacts 80 on the on-skin sensor control unit 44. Optionally, thisaction activates the on-skin sensor control unit 44 to begin operation.

[0247] On-Skin Control Unit Electronics

[0248] The on-skin sensor control unit 44 also typically includes atleast a portion of the electronic components that operate the sensor 42and the analyte monitoring device system 40. One embodiment of theelectronics in the on-skin control unit 44 is illustrated as a blockdiagram in FIG. 18A. The electronic components of the on-skin sensorcontrol unit 44 typically include a power supply 95 for operating theon-skin control unit 44 and the sensor 42, a sensor circuit 97 forobtaining signals from and operating the sensor 42, a measurementcircuit 96 that converts sensor signals to a desired format, and aprocessing circuit 109 that, at minimum, obtains signals from the sensorcircuit 97 and/or measurement circuit 96 and provides the signals to anoptional transmitter 98. In some embodiments, the processing circuit 109may also partially or completely evaluate the signals from the sensor 42and convey the resulting data to the optional transmitter 98 and/oractivate an optional alarm system 94 (see FIG. 18B) if the analyte levelexceeds a threshold. The processing circuit 109 often includes digitallogic circuitry.

[0249] The on-skin sensor control unit 44 may optionally contain atransmitter 98 for transmitting the sensor signals or processed datafrom the processing circuit 109 to a receiver/display unit 46, 48; adata storage unit 102 for temporarily or permanently storing data fromthe processing circuit 109; a temperature probe circuit 99 for receivingsignals from and operating a temperature probe 66; a reference voltagegenerator 101 for providing a reference voltage for comparison withsensor-generated signals; and/or a watchdog circuit 103 that monitorsthe operation of the electronic components in the on-skin sensor controlunit 44.

[0250] Moreover, the sensor control unit 44 often includes digitaland/or analog components utilizing semiconductor devices, such astransistors. To operate these semiconductor devices, the on-skin controlunit 44 may include other components including, for example, a biascontrol generator 105 to correctly bias analog and digital semiconductordevices, an oscillator 107 to provide a clock signal, and a digitallogic and timing component 109 to provide timing signals and logicoperations for the digital components of the circuit.

[0251] As an example of the operation of these components, the sensorcircuit 97 and the optional temperature probe circuit 99 provide rawsignals from the sensor 42 to the measurement circuit 96. Themeasurement circuit 96 converts the raw signals to a desired format,using for example, a current-to-voltage converter, current-to-frequencyconverter, and/or a binary counter or other indicator that produces asignal proportional to the absolute value of the raw signal. This may beused, for example, to convert the raw signal to a format that can beused by digital logic circuits. The processing circuit 109 may then,optionally, evaluate the data and provide commands to operate theelectronics.

[0252]FIG. 18B illustrates a block diagram of another exemplary on-skincontrol unit 44 that also includes optional components such as areceiver 99 to receive, for example, calibration data; a calibrationstorage unit 100 to hold, for example, factory-set calibration data,calibration data obtained via the receiver 99 and/or operational signalsreceived, for example, from a receiver/display unit 46, 48 or otherexternal device; an alarm system 104 for warning the patient; and adeactivation switch 111 to turn off the alarm system.

[0253] Functions of the analyte monitoring system 40 and the sensorcontrol unit 44 may be implemented using either software routines,hardware components, or combinations thereof. The hardware componentsmay be implemented using a variety of technologies, including, forexample, integrated circuits or discrete electronic components. The useof integrated circuits typically reduces the size of the electronics,which in turn may result in a smaller on-skin sensor control unit 44.

[0254] The electronics in the on-skin sensor control unit 44 and thesensor 42 are operated using a power supply 95. One example of asuitable power supply 95 is a battery, for example, a thin circularbattery, such as those used in many watches, hearing aids, and othersmall electronic devices. Preferably, the battery has a lifetime of atleast 30 days, more preferably, a lifetime of at least three months, andmost preferably, a lifetime of at least one year. The battery is oftenone of the largest components in the on-skin control unit 44, so it isoften desirable to minimize the size of the battery. For example, apreferred battery's thickness is 0.5 mm or less, preferably 0.35 mm orless, and most preferably 0.2 mm or less. Although multiple batteriesmay be used, it is typically preferred to use only one battery.

[0255] The sensor circuit 97 is coupled via the conductive contacts 80of the sensor control unit 44 to one or more sensors 42, 42′. Each ofthe sensors represents, at minimum, a working electrode 58, a counterelectrode 60 (or counter/reference electrode), and an optional referenceelectrode 62. When two or more sensors 42, 42′ are used, the sensorstypically have individual working electrodes 58, but may share a counterelectrode 60, counter/reference electrode, and/or reference electrode52.

[0256] The sensor circuit 97 receives signals from and operates thesensor 42 or sensors 42, 42′. The sensor circuit 97 may obtain signalsfrom the sensor 42 using amperometric, coulometric, potentiometric,voltammetric, and/or other electrochemical techniques. The sensorcircuit 97 is exemplified herein as obtaining amperometric signals fromthe sensor 42, however, it will be understood that the sensor circuitcan be appropriately configured for obtaining signals using otherelectrochemical techniques. To obtain amperometric measurements, thesensor circuit 97 typically includes a potentiostat that provides aconstant potential to the sensor 42. In other embodiments, the sensorcircuit 97 includes an amperostat that supplies a constant current tothe sensor 42 and can be used to obtain coulometric or potentiometricmeasurements.

[0257] The signal from the sensor 42 generally has at least onecharacteristic, such as, for example, current, voltage, or frequency,which varies with the concentration of the analyte. For example, if thesensor circuit 97 operates using amperometry, then the signal currentvaries with analyte concentration. The measurement circuit 96 mayinclude circuitry which converts the information-carrying portion of thesignal from one characteristic to another. For example, the measurementcircuit 96 may include a current-to-voltage or current-to-frequencyconverter. The purpose of this conversion may be to provide a signalthat is, for example, more easily transmitted, readable by digitalcircuits, and/or less susceptible to noise contributions.

[0258] One example of a standard current-to-voltage converter isprovided in FIG. 20A. In this converter, the signal from the sensor 42is provided at one input terminal 134 of an operational amplifier 130(“op amp”) and coupled through a resistor 138 to an output terminal 136.This particular current-to-voltage converter 131 may, however, bedifficult to implement in a small CMOS chip because resistors are oftendifficult to implement on an integrated circuit. Typically, discreteresistor components are used. However, the used of discrete componentsincreases the space needed for the circuitry.

[0259] An alternative current-to-voltage converter 141 is illustrated inFIG. 20B. This converter includes an op amp 140 with the signal from thesensor 42 provided at input terminal 144 and a reference potentialprovided at input terminal 142. A capacitor 145 is placed between theinput terminal 144 and the output terminal 146. In addition, switches147 a, 147 b, 149 a, and 149 b are provided to allow the capacitor tocharge and discharge at a rate determined by a clock (CLK) frequency. Inoperation, during one half cycle, switches 147 a and 147 b close andswitches 149 a and 149 b open allowing the capacitor 145 to charge dueto the attached potential V1. During the other half cycle, switches 147a and 147 b open and switches 149 a and 149 b close to ground and allowthe capacitor 145 to partially or fully discharge. The reactiveimpedance of the capacitor 145 is analogous to the resistance of theresistor 138 (see FIG. 20A), allowing the capacitor 145 to emulate aresistor. The value of this “resistor” depends on the capacitance of thecapacitor 145 and the clock frequency. By altering the clock frequency,the reactive impedance (“resistance value”) of the capacitor changes.The value of the impedance (“resistance”) of the capacitor 145 may bealtered by changing the clock frequency. Switches 147 a, 147 b, 149 a,and 149 b may be implemented in a CMOS chip using, for example,transistors.

[0260] A current-to-frequency converter may also be used in themeasurement circuit 96. One suitable current-to-frequency converterincludes charging a capacitor using the signal from the sensor 42. Whenthe potential across the capacitor exceeds a threshold value, thecapacitor is allowed to discharge. Thus, the larger the current from thesensor 42, the quicker the threshold potential is achieved. This resultsin a signal across the capacitor that has an alternating characteristic,corresponding to the charging and discharging of the capacitor, having afrequency which increases with an increase in current from the sensor42.

[0261] In some embodiments, the analyte monitoring system 40 includestwo or more working electrodes 58 distributed over one or more sensors42. These working electrodes 58 may be used for quality controlpurposes. For example, the output signals and/or analyzed data derivedusing the two or more working electrodes 58 may be compared to determineif the signals from the working electrodes agree within a desired levelof tolerance. If the output signals do not agree, then the patient maybe alerted to replace the sensor or sensors. In some embodiments, thepatient is alerted only if the lack of agreement between the two sensorspersists for a predetermined period of time. The comparison of the twosignals may be made for each measurement or at regular intervals.Alternatively or additionally, the comparison may be initiated by thepatient or another person. Moreover, the signals from both sensors maybe used to generate data or one signal may be discarded after thecomparison.

[0262] Alternatively, if, for example, two working electrodes 58 have acommon counter electrode 60 and the analyte concentration is measured byamperometry, then the current at the counter electrode 60 should betwice the current at each of the working electrodes, within apredetermined tolerance level, if the working electrodes are operatingproperly. If not, then the sensor or sensors should be replaced, asdescribed above.

[0263] An example of using signals from only one working electrode forquality control includes comparing consecutive readings obtained usingthe single working electrode to determine if they differ by more than athreshold level. If the difference is greater than the threshold levelfor one reading or over a period of time or for a predetermined numberof readings within a period of time then the patient is alerted toreplace the sensor 42. Typically, the consecutive readings and/or thethreshold level are determined such that all expected excursions of thesensor signal are within the desired parameters (i.e., the sensorcontrol unit 44 does not consider true changes in analyte concentrationto be a sensor failure).

[0264] The sensor control unit 44 may also optionally include atemperature probe circuit 99. The temperature probe circuit 99 providesa constant current through (or constant potential) across thetemperature probe 66. The resulting potential (or current) variesaccording to the resistance of the temperature dependent element 72.

[0265] The output from the sensor circuit 97 and optional temperatureprobe circuit is coupled into a measurement circuit 96 that obtainssignals from the sensor circuit 97 and optional temperature probecircuit 99 and, at least in some embodiments, provides output data in aform that, for example can be read by digital circuits. The signals fromthe measurement circuit 96 are sent to the processing circuit 109, whichin turn may provide data to an optional transmitter 98. The processingcircuit 109 may have one or more of the following functions: 1) transferthe signals from the measurement circuit 96 to the transmitter 98, 2)transfer signals from the measurement circuit 96 to the data storagecircuit 102, 3) convert the information-carrying characteristic of thesignals from one characteristic to another (when, for example, that hasnot been done by the measurement circuit 96), using, for example, acurrent-to-voltage converter, a current-to-frequency converter, or avoltage-to-current converter, 4) modify the signals from the sensorcircuit 97 using calibration data and/or output from the temperatureprobe circuit 99, 5) determine a level of an analyte in the interstitialfluid, 6) determine a level of an analyte in the bloodstream based onthe sensor signals obtained from interstitial fluid, 7) determine if thelevel, rate of change, and/or acceleration in the rate of change of theanalyte exceeds or meets one or more threshold values, 8) activate analarm if a threshold value is met or exceeded, 9) evaluate trends in thelevel of an analyte based on a series of sensor signals, 10) determine adose of a medication, and 11) reduce noise and/or errors, for example,through signal averaging or comparing readings from multiple workingelectrodes 58.

[0266] The processing circuit 109 may be simple and perform only one ora small number of these functions or the processing circuit 109 may bemore sophisticated and perform all or most of these functions. The sizeof the on-skin sensor control unit 44 may increase with the increasingnumber of functions and complexity of those functions that theprocessing circuit 109 performs. Many of these functions may not beperformed by a processing circuit 109 in the on-skin sensor control unit44, but may be performed by another analyzer 152 in the receiver/displayunits 46, 48 (see FIG. 22).

[0267] One embodiment of the measurement circuit 96 and/or processingcircuit 109 provides as output data, the current flowing between theworking electrode 58 and the counter electrode 60. The measurementcircuit 96 and/or processing circuit 109 may also provide as output dataa signal from the optional temperature probe 66 which indicates thetemperature of the sensor 42. This signal from the temperature probe 66may be as simple as a current through the temperature probe 66 or theprocessing circuit 109 may include a device that determines a resistanceof the temperature probe 66 from the signal obtained from themeasurement circuit 96 for correlation with the temperature of thesensor 42. The output data may then be sent to a transmitter 98 thatthen transmits this data to at least one receiver/display device 46,48.

[0268] Returning to the processing circuit 109, in some embodimentsprocessing circuit 109 is more sophisticated and is capable ofdetermining the analyte concentration or some measure representative ofthe analyte concentration, such as a current or voltage value. Theprocessing circuit 109 may incorporate the signal of the temperatureprobe to make a temperature correction in the signal or analyzed datafrom the working electrode 58. This may include, for example, scalingthe temperature probe measurement and adding or subtracting the scaledmeasurement to the signal or analyzed data from the working electrode58. The processing circuit 109 may also incorporate calibration datawhich has been received from an external source or has been incorporatedinto the processing circuit 109, both of which are described below, tocorrect the signal or analyzed data from the working electrode 58.Additionally, the processing circuit 109 may include a correctionalgorithm for converting interstitial analyte level to blood analytelevel. The conversion of interstitial analyte level to blood analytelevel is described, for example, in Schmidtke, et al., “Measurement andModeling of the Transient Difference Between Blood and SubcutaneousGlucose Concentrations in the Rat after Injection of Insulin”, Proc. ofthe Nat'l Acad. of Science, 95, 294-299 (1998) and Quinn, et al.,“Kinetics of Glucose Delivery to Subcutaneous Tissue in Rats Measuredwith 0.3 mm Amperometric Microsensors”, Am. J. Physiol., 269(Endocrinol. Metab. 32), E155-E161 (1995), incorporated herein byreference.

[0269] In some embodiments, the data from the processing circuit 109 isanalyzed and directed to an alarm system 94 (see FIG. 18B) to warn theuser. In at least some of these embodiments, a transmitter is not usedas the sensor control unit performs all of the needed functionsincluding analyzing the data and warning the patient.

[0270] However, in many embodiments, the data (e.g., a current signal, aconverted voltage or frequency signal, or fully or partially analyzeddata) from processing circuit 109 is transmitted to one or morereceiver/display units 46, 48 using a transmitter 98 in the on-skinsensor control unit 44. The transmitter has an antenna 93, such as awire or similar conductor, formed in the housing 45. The transmitter 98is typically designed to transmit a signal up to about 2 meters or more,preferably up to about 5 meters or more, and more preferably up to about10 meters or more, when transmitting to a small receiver/display unit46, such as a palm-size, belt-worn receiver. The effective range islonger when transmitting to a unit with a better antenna, such as abedside receiver. As described in detail below, suitable examples ofreceiver/display units 46, 48 include units that can be easily worn orcarried or units that can be placed conveniently on, for example, anightstand when the patient is sleeping.

[0271] The transmitter 98 may send a variety of different signals to thereceiver/display units 46, 48, typically, depending on thesophistication of the processing circuit 109. For example, theprocessing circuit 109 may simply provide raw signals, for example,currents from the working electrodes 58, without any corrections fortemperature or calibration, or the processing circuit 109 may provideconverted signals which are obtained, for example, using acurrent-to-voltage converter 131 or 141 or a current-to-frequencyconverter. The raw measurements or converted signals may then beprocessed by an analyzer 152 (see FIG. 22) in the receiver/display units46, 48 to determine the level of an analyte, optionally usingtemperature and calibration corrections. In another embodiment, theprocessing circuit 109 corrects the raw measurements using, for example,temperature and/or calibration information and then the transmitter 98sends the corrected signal, and optionally, the temperature and/orcalibration information, to the receiver/display units 46, 48. In yetanother embodiment, the processing circuit 109 calculates the analytelevel in the interstitial fluid and/or in the blood (based on theinterstitial fluid level) and transmits that information to the one ormore receiver/display units 46, 48, optionally with any of the raw dataand/or calibration or temperature information. In a further embodiment,the processing circuit 109 calculates the analyte concentration, but thetransmitter 98 transmits only the raw measurements, converted signals,and/or corrected signals.

[0272] One potential difficulty that may be experienced with the on-skinsensor control unit 44 is a change in the transmission frequency of thetransmitter 98 over time. To overcome this potential difficulty, thetransmitter may include optional circuitry that can return the frequencyof the transmitter 98 to the desired frequency or frequency band. Oneexample of suitable circuitry is illustrated in FIG. 21 as a blockdiagram of an open loop modulation system 200. The open loop modulationsystem 200 includes a phase detector (PD) 210, a charge pump (CHGPMP)212, a loop filter (L.F.) 214, a voltage controlled oscillator (VCO)216, and a divide by M circuit (÷M) 218 to form the phase-locked loop220.

[0273] The analyte monitoring device 40 uses an open loop modulationsystem 200 for RF communication between the transmitter 98 and areceiver of, for example, the one or more receiver/display units 46, 48.This open loop modulation system 230 is designed to provide a highreliability RF link between a transmitter and its associated receiver.The system employs frequency modulation (FM), and locks the carriercenter frequency using a conventional phase-locked loop (PLL) 220. Inoperation, the phase-locked loop 220 is opened prior to the modulation.During the modulation the phase-locked loop 220 remains open for as longas the center frequency of the transmitter is within the receiver'sbandwidth. When the transmitter detects that the center frequency isgoing to move outside of the receiver bandwidth, the receiver issignaled to stand by while the center frequency is captured. Subsequentto the capture, the transmission will resume. This cycle of capturingthe center frequency, opening the phase-locked loop 220, modulation, andrecapturing the center frequency will repeat for as many cycles asrequired.

[0274] The loop control 240 detects the lock condition of thephase-locked loop 220 and is responsible for closing and opening thephase-locked loop 220. The totalizer 250 in conjunction with the loopcontrol 240, detects the status of the center frequency. The modulationcontrol 230 is responsible for generating the modulating signal. Atransmit amplifier 260 is provided to ensure adequate transmit signalpower. The reference frequency is generated from a very stable signalsource (not shown), and is divided down by N through the divide by Nblock (÷N) 270. Data and control signals are received by the open loopmodulation system 200 via the DATA BUS 280, and the CONTROL BUS 290.

[0275] The operation of the open loop modulation system 200 begins withthe phase-locked loop 220 in closed condition. When the lock conditionis detected by the loop control 240, the phase-locked loop 220 is openedand the modulation control 230 begins generating the modulating signal.The totalizer 250 monitors the VCO frequency (divided by M), forprogrammed intervals. The monitored frequency is compared to a thresholdprogrammed in the totalizer 250. This threshold corresponds to the 3 dBcut off frequencies of the receiver's intermediate frequency stage. Whenthe monitored frequency approaches the thresholds, the loop control 240is notified and a stand-by code is transmitted to the receiver and thephase-locked loop 220 is closed.

[0276] At this point the receiver is in the wait mode. The loop control240 in the transmitter closes the phase-locked loop 220. Then,modulation control 230 is taken off line, the monitored value of thetotalizer 250 is reset, and the phase-locked loop 220 is locked. Whenthe loop control 240 detects a lock condition, the loop control 240opens the phase-locked loop 220, the modulation control 230 is broughton line and the data transmission to the receiver will resume until thecenter frequency of the phase-locked loop 220 approaches the thresholdvalues, at which point the cycle of transmitting the stand-by codebegins. The ÷N 270 and ÷M 218 block set the frequency channel of thetransmitter.

[0277] Accordingly, the open loop modulation system 200 provides areliable low power FM data transmission for an analyte monitoringsystem. The open loop modulation system 200 provides a method of wideband frequency modulation, while the center frequency of the carrier iskept within receiver bandwidth. The effect of parasitic capacitors andinductors pulling the center frequency of the transmitter is correctedby the phase-locked loop 220. Further, the totalizer 250 and loopcontrol 240 provide a new method of center frequency drift detection.Finally, the open loop modulation system 200 is easily implemented inCMOS process.

[0278] The rate at which the transmitter 98 transmits data may be thesame rate at which the sensor circuit 97 obtains signals and/or theprocessing circuit 109 provides data or signals to the transmitter 98.Alternatively, the transmitter 98 may transmit data at a slower rate. Inthis case, the transmitter 98 may transmit more than one datapoint ineach transmission. Alternatively, only one datapoint may be sent witheach data transmission, the remaining data not being transmitted.Typically, data is transmitted to the receiver/display unit 46, 48 atleast every hour, preferably, at least every fifteen minutes, morepreferably, at least every five minutes, and most preferably, at leastevery one minute. However, other data transmission rates may be used. Insome embodiments, the processing circuit 109 and/or transmitter 98 areconfigured to process and/or transmit data at a faster rate when acondition is indicated, for example, a low level or high level ofanalyte or impending low or high level of analyte. In these embodiments,the accelerated data transmission rate is typically at least every fiveminutes and preferably at least every minute.

[0279] In addition to a transmitter 98, an optional receiver 99 may beincluded in the on-skin sensor control unit 44. In some cases, thetransmitter 98 is a transceiver, operating as both a transmitter and areceiver. The receiver 99 may be used to receive calibration data forthe sensor 42. The calibration data may be used by the processingcircuit 109 to correct signals from the sensor 42. This calibration datamay be transmitted by the receiver/display unit 46, 48 or from someother source such as a control unit in a doctor's office. In addition,the optional receiver 99 may be used to receive a signal from thereceiver/display units 46, 48, as described above, to direct thetransmitter 98, for example, to change frequencies or frequency bands,to activate or deactivate the optional alarm system 94 (as describedbelow), and/or to direct the transmitter 98 to transmit at a higherrate.

[0280] Calibration data may be obtained in a variety of ways. Forinstance, the calibration data may simply be factory-determinedcalibration measurements which can be input into the on-skin sensorcontrol unit 44 using the receiver 99 or may alternatively be stored ina calibration data storage unit 100 within the on-skin sensor controlunit 44 itself (in which case a receiver 99 may not be needed). Thecalibration data storage unit 100 may be, for example, a readable orreadable/writeable memory circuit.

[0281] Alternative or additional calibration data may be provided basedon tests performed by a doctor or some other professional or by thepatient himself. For example, it is common for diabetic individuals todetermine their own blood glucose concentration using commerciallyavailable testing kits. The results of this test is input into theon-skin sensor control unit 44 either directly, if an appropriate inputdevice (e.g., a keypad, an optical signal receiver, or a port forconnection to a keypad or computer) is incorporated in the on-skinsensor control unit 44, or indirectly by inputting the calibration datainto the receiver/display unit 46, 48 and transmitting the calibrationdata to the on-skin sensor control unit 44.

[0282] Other methods of independently determining analyte levels mayalso be used to obtain calibration data. This type of calibration datamay supplant or supplement factory-determined calibration values.

[0283] In some embodiments of the invention, calibration data may berequired at periodic intervals, for example, every eight hours, once aday, or once a week, to confirm that accurate analyte levels are beingreported. Calibration may also be required each time a new sensor 42 isimplanted or if the sensor exceeds a threshold minimum or maximum valueor if the rate of change in the sensor signal exceeds a threshold value.In some cases, it may be necessary to wait a period of time after theimplantation of the sensor 42 before calibrating to allow the sensor 42to achieve equilibrium. In some embodiments, the sensor 42 is calibratedonly after it has been inserted. In other embodiments, no calibration ofthe sensor 42 is needed.

[0284] The on-skin sensor control unit 44 and/or a receiver/display unit46, 48 may include an auditory or visual indicator that calibration datais needed, based, for example, on a predetermined periodic time intervalbetween calibrations or on the implantation of a new sensor 42. Theon-skin sensor control unit 44 and/or receiver display/units 46, 48 mayalso include an auditory or visual indicator to remind the patient thatinformation, such as analyte levels, reported by the analyte monitoringdevice 40, may not be accurate because a calibration of the sensor 42has not been performed within the predetermined periodic time intervaland/or after implantation of a new sensor 42.

[0285] The processing circuit 109 of the on-skin sensor control unit 44and/or an analyzer 152 of the receiver/display unit 46, 48 may determinewhen calibration data is needed and if the calibration data isacceptable. The on-skin sensor control unit 44 may optionally beconfigured to not allow calibration or to reject a calibration point if,for example, 1) a temperature reading from the temperature probeindicates a temperature that is not within a predetermined acceptablerange (e.g., 30 to 42° C. or 32 to 40° C.) or that is changing rapidly(for example, 0.2° C./minute, 0.5° C./minute, or 0.7° C./minute orgreater); 2) two or more working electrodes 58 provide uncalibratedsignals that are not within a predetermined range (e.g., within 10% or20%) of each other; 3) the rate of change of the uncalibrated signal isabove a threshold rate (e.g., 0.25 mg/dL per minute or 0.5 mg/dL perminute or greater); 4) the uncalibrated signal exceeds a thresholdmaximum value (e.g., 5, 10, 20, or 40 nA) or is below a thresholdminimum value (e.g., 0.05, 0.2, 0.5, or 1 nA); 5) the calibrated signalexceeds a threshold maximum value (e.g., a signal corresponding to ananalyte concentration of 200 mg/dL, 250 mg/dL, or 300 mg/dL) or is belowa threshold minimum value (e.g., a signal corresponding to an analyteconcentration of 50 mg/dL, 65 mg/dL, or 80 mg/dL); and/or 6) aninsufficient among of time has elapsed since implantation (e.g., 10minutes or less, 20 minutes or less, or 30 minutes or less).

[0286] The processing circuit 109 or an analyzer 152 may also requestanother calibration point if the values determined using the sensor databefore and after the latest calibration disagree by more than athreshold amount, indicating that the calibration may be incorrect orthat the sensor characteristics have changed radically betweencalibrations. This additional calibration point may indicate the sourceof the difference.

[0287] The on-skin sensor control unit 44 may include an optional datastorage unit 102 which may be used to hold data (e.g., measurements fromthe sensor or processed data) from the processing circuit 109permanently or, more typically, temporarily. The data storage unit 102may hold data so that the data can be used by the processing circuit 109to analyze and/or predict trends in the analyte level, including, forexample, the rate and/or acceleration of analyte level increase ordecrease. The data storage unit 102 may also or alternatively be used tostore data during periods in which a receiver/display unit 46, 48 is notwithin range. The data storage unit 102 may also be used to store datawhen the transmission rate of the data is slower than the acquisitionrate of the data. For example, if the data acquisition rate is 10points/min and the transmission is 2 transmissions/min, then one to fivepoints of data could be sent in each transmission depending on thedesired rate for processing datapoints. The data storage unit 102typically includes a readable/writeable memory storage device andtypically also includes the hardware and/or software to write to and/orread the memory storage device.

[0288] The on-skin sensor control unit 44 may include an optional alarmsystem 104 that, based on the data from the processing circuit 109,warns the patient of a potentially detrimental condition of the analyte.For example, if glucose is the analyte, than the on-skin sensor controlunit 44 may include an alarm system 104 that warns the patient ofconditions such as hypoglycemia, hyperglycemia, impending hypoglycemia,and/or impending hyperglycemia. The alarm system 104 is triggered whenthe data from the processing circuit 109 reaches or exceeds a thresholdvalue. Examples of threshold values for blood glucose levels are about60, 70, or 80 mg/dL for hypoglycemia; about 70, 80, or 90 mg/dL forimpending hypoglycemia; about 130, 150, 175, 200, 225, 250, or 275 mg/dLfor impending hyperglycemia; and about 150, 175, 200, 225, 250, 275, or300 mg/dL for hyperglycemia. The actual threshold values that aredesigned into the alarm system 104 may correspond to interstitial fluidglucose concentrations or electrode measurements (e.g., current valuesor voltage values obtained by conversion of current measurements) thatcorrelate to the above-mentioned blood glucose levels. The analytemonitor device may be configured so that the threshold levels for theseor any other conditions may be programmable by the patient and/or amedical professional.

[0289] A threshold value is exceeded if the datapoint has a value thatis beyond the threshold value in a direction indicating a particularcondition. For example, a datapoint which correlates to a glucose levelof 200 mg/dL exceeds a threshold value for hyperglycemia of 180 mg/dL,because the datapoint indicates that the patient has entered ahyperglycemic state. As another example, a datapoint which correlates toa glucose level of 65 mg/dL exceeds a threshold value for hypoglycemiaof 70 mg/dL because the datapoint indicates that the patient ishypoglycemic as defined by the threshold value. However, a datapointwhich correlates to a glucose level of 75 mg/dL would not exceed thesame threshold value for hypoglycemia because the datapoint does notindicate that particular condition as defined by the chosen thresholdvalue.

[0290] An alarm may also be activated if the sensor readings indicate avalue that is beyond a measurement range of the sensor 42. For glucose,the physiologically relevant measurement range is typically about 50 to250 mg/dL, preferably about 40-300 mg/dL and ideally 30-400 mg/dL, ofglucose in the interstitial fluid.

[0291] The alarm system 104 may also, or alternatively, be activatedwhen the rate of change or acceleration of the rate of change in analytelevel increase or decrease reaches or exceeds a threshold rate oracceleration. For example, in the case of a subcutaneous glucosemonitor, the alarm system might be activated if the rate of change inglucose concentration exceeds a threshold value which might indicatethat a hyperglycemic or hypoglycemic condition is likely to occur.

[0292] The optional alarm system 104 may be configured to activate whena single data point meets or exceeds a particular threshold value.Alternatively, the alarm may be activated only when a predeterminednumber of datapoints spanning a predetermined amount of time meet orexceed the threshold value. As another alternative, the alarm may beactivated only when the datapoints spanning a predetermined amount oftime have an average value which meets or exceeds the threshold value.Each condition that can trigger an alarm may have a different alarmactivation condition. In addition, the alarm activation condition maychange depending on current conditions (e.g., an indication of impendinghyperglycemia may alter the number of datapoints or the amount of timethat is tested to determine hyperglycemia).

[0293] The alarm system 104 may contain one or more individual alarms.Each of the alarms may be individually activated to indicate one or moreconditions of the analyte. The alarms may be, for example, auditory orvisual. Other sensory-stimulating alarm systems may be used includingalarm systems which heat, cool, vibrate, or produce a mild electricalshock when activated. In some embodiments, the alarms are auditory witha different tone, note, or volume indicating different conditions. Forexample, a high note might indicate hyperglycemia and a low note mightindicate hypoglycemia. Visual alarms may use a difference in color,brightness, or position on the on-skin sensor control device 44 toindicate different conditions. In some embodiments, an auditory alarmsystem is configured so that the volume of the alarm increases over timeuntil the alarm is deactivated.

[0294] In some embodiments, the alarm may be automatically deactivatedafter a predetermined time period. In other embodiments, the alarm maybe configured to deactivate when the data no longer indicate that thecondition which triggered the alarm exists. In these embodiments, thealarm may be deactivated when a single data point indicates that thecondition no longer exists or, alternatively, the alarm may bedeactivated only after a predetermined number of datapoints or anaverage of datapoints obtained over a given period of time indicate thatthe condition no longer exists.

[0295] In some embodiments, the alarm may be deactivated manually by thepatient or another person in addition to or as an alternative toautomatic deactivation. In these embodiments, a switch 101 is providedwhich when activated turns off the alarm. The switch 101 may beoperatively engaged (or disengaged depending on the configuration of theswitch) by, for example, operating an actuator on the on-skin sensorcontrol unit 44 or the receiver/display unit 46, 48. In some cases, anactuator may be provided on two or more units 44, 46, 48, any of whichmay be actuated to deactivate the alarm. If the switch 101 and oractuator is provided on the receiver/display unit 46, 48 then a signalmay be transmitted from the receiver/display unit 46, 48 to the receiver98 on the on-skin sensor control unit 44 to deactivate the alarm.

[0296] A variety of switches 101 may be used including, for example, amechanical switch, a reed switch, a Hall effect switch, a GiganticMagnetic Ratio (GMR) switch (the resistance of the GMR switch ismagnetic field dependent) and the like. Preferably, the actuator used tooperatively engage (or disengage) the switch is placed on the on-skinsensor control unit 44 and configured so that no water can flow aroundthe button and into the housing. One example of such a button is aflexible conducting strip that is completely covered by a flexiblepolymeric or plastic coating integral to the housing. In an openposition the flexible conducting strip is bowed and bulges away from thehousing. When depressed by the patient or another person, the flexibleconducting strip is pushed directly toward a metal contact and completesthe circuit to shut off the alarm.

[0297] For a reed or GMR switch, a piece of magnetic material, such as apermanent magnet or an electromagnet, in a flexible actuator that isbowed or bulges away from the housing 45 and the reed or GMR switch isused. The reed or GMR switch is activated (to deactivate the alarm) bydepressing the flexible actuator bringing the magnetic material closerto the switch and causing an increase in the magnetic field within theswitch.

[0298] In some embodiments of the invention, the analyte monitoringdevice 40 includes only an on-skin control unit 44 and a sensor 42. Inthese embodiments, the processing circuit 109 of the on-skin sensorcontrol unit 44 is able to determine a level of the analyte and activatean alarm system 104 if the analyte level exceeds a threshold. Theon-skin control unit 44, in these embodiments, has an alarm system 104and may also include a display, such as those discussed below withrespect to the receiver/display units 46, 48. Preferably, the display isan LCD or LED display. The on-skin control unit 44 may not have atransmitter, unless, for example, it is desirable to transmit data, forexample, to a control unit in a doctor's office.

[0299] The on-skin sensor control unit 44 may also include a referencevoltage generator 101 to provide an absolute voltage or current for usein comparison to voltages or currents obtained from or used with thesensor 42. An example of a suitable reference voltage generator is aband-gap reference voltage generator that uses, for example, asemiconductor material with a known band-gap. Preferably, the band-gapis temperature insensitive over the range of temperatures that thesemiconductor material will experience during operation. Suitablesemiconductor materials includes gallium, silicon and silicates.

[0300] A bias current generator 105 may be provided to correctly biassolid-state electronic components. An oscillator 107 may be provided toproduce a clock signal that is typically used with digital circuitry.

[0301] The on-skin sensor control unit 44 may also include a watchdogcircuit 103 that tests the circuitry, particularly, any digitalcircuitry in the control unit 44 to determine if the circuitry isoperating correctly. Non-limiting examples of watchdog circuitoperations include: a) generation of a random number by the watchdogcircuit, storage of the number in a memory location, writing the numberto a register in the watchdog circuit, and recall of the number tocompare for equality; b) checking the output of an analog circuit todetermine if the output exceeds a predetermined dynamic range; c)checking the output of a timing circuit for a signal at an expectedpulse interval. Other examples of functions of a watchdog circuit areknown in the art. If the watchdog circuit detects an error that watchdogcircuit may activate an alarm and/or shut down the device.

[0302] Receiver/Display Unit

[0303] One or more receiver/display units 46, 48 may be provided withthe analyte monitoring device 40 for easy access to the data generatedby the sensor 42 and may, in some embodiments, process the signals fromthe on-skin sensor control unit 44 to determine the concentration orlevel of analyte in the subcutaneous tissue. Small receiver/displayunits 46 may be carried by the patient. These units 46 may be palm-sizedand/or may be adapted to fit on a belt or within a bag or purse that thepatient carries. One embodiment of the small receiver/display unit 46has the appearance of a pager, for example, so that the user is notidentified as a person using a medical device. Such receiver/displayunits may optionally have one-way or two-way paging capabilities.

[0304] Large receiver/display units 48 may also be used. These largerunits 48 may be designed to sit on a shelf or nightstand. The largereceiver/display unit 48 may be used by parents to monitor theirchildren while they sleep or to awaken patients during the night. Inaddition, the large receiver/display unit 48 may include a lamp, clock,or radio for convenience and/or for activation as an alarm. One or bothtypes of receiver/display units 46, 48 may be used.

[0305] The receiver/display units 46, 48, as illustrated in block format FIG. 22, typically include a receiver 150 to receive data from theon-skin sensor control unit 44, an analyzer 152 to evaluate the data, adisplay 154 to provide information to the patient, and an alarm system156 to warn the patient when a condition arises. The receiver/displayunits 46, 48 may also optionally include a data storage device 158, atransmitter 160, and/or an input device 162. The receiver/display units46,48 may also include other components (not shown), such as a powersupply (e.g., a battery and/or a power supply that can receive powerfrom a wall outlet), a watchdog circuit, a bias current generator, andan oscillator. These additional components are similar to thosedescribed above for the on-skin sensor control unit 44.

[0306] In one embodiment, a receiver/display unit 48 is a bedside unitfor use by a patient at home. The bedside unit includes a receiver andone or more optional items, including, for example, a clock, a lamp, anauditory alarm, a telephone connection, and a radio. The bedside unitalso has a display, preferably, with large numbers and/or letters thatcan be read across a room. The unit may be operable by plugging into anoutlet and may optionally have a battery as backup. Typically, thebedside unit has a better antenna than a small palm-size unit, so thebedside unit's reception range is longer.

[0307] When an alarm is indicated, the bedside unit may activate, forexample, the auditory alarm, the radio, the lamp, and/or initiate atelephone call. The alarm may be more intense than the alarm of a smallpalm-size unit to, for example, awaken or stimulate a patient who may beasleep, lethargic, or confused. Moreover, a loud alarm may alert aparent monitoring a diabetic child at night.

[0308] The bedside unit may have its own data analyzer and data storage.The data may be communicated from the on-skin sensor unit or anotherreceiver/display unit, such as a palm-size or small receiver/displayunit. Thus, at least one unit has all the relevant data so that the datacan be downloaded and analyzed without significant gaps.

[0309] Optionally, the beside unit has an interface or cradle into whicha small receiver/display unit may be placed. The bedside unit may becapable of utilizing the data storage and analysis capabilities of thesmall receiver/display unit and/or receive data from the smallreceiver/display unit in this position. The bedside unit may also becapable of recharging a battery of the small receiver/display unit.

[0310] The receiver 150 typically is formed using known receiver andantenna circuitry and is often tuned or tunable to the frequency orfrequency band of the transmitter 98 in the on-skin sensor control unit44. Typically, the receiver 150 is capable of receiving signals from adistance greater than the transmitting distance of the transmitter 98.The small receiver/display unit 46 can typically receive a signal froman on-skin sensor control unit 44 that is up to 2 meters, preferably upto 5 meters, and more preferably up to 10 meters or more, away. A largereceiver/display unit 48, such as a bedside unit, can typically receivea receive a signal from an on-skin sensor control unit 44 that is up to5 meters distant, preferably up to 10 meters distant, and morepreferably up to 20 meters distant or more.

[0311] In one embodiment, a repeater unit (not shown) is used to boost asignal from an on-skin sensor control unit 44 so that the signal can bereceived by a receiver/display unit 46, 48 that may be distant from theon-skin sensor control unit 44. The repeater unit is typicallyindependent of the on-skin sensor control unit 44, but, in some cases,the repeater unit may be configured to attach to the on-skin sensorcontrol unit 44. Typically, the repeater unit includes a receiver forreceiving the signals from the on-skin sensor control unit 44 and atransmitter for transmitting the received signals. Often the transmitterof the repeater unit is more powerful than the transmitter of theon-skin sensor control unit, although this is not necessary. Therepeater unit may be used, for example, in a child's bedroom fortransmitting a signal from an on-skin sensor control unit on the childto a receiver/display unit in the parent's bedroom for monitoring thechild's analyte levels. Another exemplary use is in a hospital with adisplay/receiver unit at a nurse's station for monitoring on-skin sensorcontrol unit(s) of patients.

[0312] The presence of other devices, including other on-skin sensorcontrol units, may create noise or interference within the frequencyband of the transmitter 98. This may result in the generation of falsedata. To overcome this potential difficulty, the transmitter 98 may alsotransmit a code to indicate, for example, the beginning of atransmission and/or to identify, preferably using a uniqueidentification code, the particular on-skin sensor control unit 44 inthe event that there is more than one on-skin sensor control unit 44 orother transmission source within range of the receiver/display unit 46,48. The provision of an identification code with the data may reduce thelikelihood that the receiver/display unit 46, 48 intercepts andinterprets signals from other transmission sources, as well aspreventing “crosstalk” with different on-skin sensor control units 44.The identification code may be provided as a factory-set code stored inthe sensor control unit 44. Alternatively, the identification code maybe randomly generated by an appropriate circuit in the sensor controlunit 44 or the receiver/display unit 46, 48 (and transmitted to thesensor control unit 44) or the identification code may be selected bythe patient and communicated to the sensor control unit 44 via atransmitter or an input device coupled to the sensor control unit 44.

[0313] Other methods may be used to eliminate “crosstalk” and toidentify signals from the appropriate on-skin sensor control unit 44. Insome embodiments, the transmitter 98 may use encryption techniques toencrypt the datastream from the transmitter 98. The receiver/displayunit 46, 48 contains the key to decipher the encrypted data signal. Thereceiver/display unit 46, 48 then determines when false signals or“crosstalk” signals are received by evaluation of the signal after ithas been deciphered. For example, the analyzer 152 in the one or morereceiver/display units 46, 48 compares the data, such as currentmeasurements or analyte levels, with expected measurements (e.g., anexpected range of measurements corresponding to physiologically relevantanalyte levels). Alternatively, an analyzer in the receiver/displayunits 46, 48 searches for an identification code in the decrypted datasignal.

[0314] Another method to eliminate “crosstalk”, which is typically usedin conjunction with the identification code or encryption scheme,includes providing an optional mechanism in the on-skin sensor controlunit 44 for changing transmission frequency or frequency bands upondetermination that there is “crosstalk”. This mechanism for changing thetransmission frequency or frequency band may be initiated by thereceiver/display unit automatically, upon detection of the possibilityof cross-talk or interference, and/or by a patient manually. Forautomatic initiation, the receiver/display unit 46, 48 transmits asignal to the optional receiver 99 on the on-skin sensor control unit 44to direct the transmitter 98 of the on-skin sensor control unit 44 tochange frequency or frequency band.

[0315] Manual initiation of the change in frequency or frequency bandmay be accomplished using, for example, an actuator (not shown) on thereceiver/display unit 46, 48 and/or on the on-skin sensor control unit44 which a patient operates to direct the transmitter 98 to changefrequency or frequency band. The operation of a manually initiatedchange in transmission frequency or frequency band may include promptingthe patient to initiate the change in frequency or frequency band by anaudio or visual signal from the receiver/display unit 46, 48 and/oron-skin sensor control unit 44.

[0316] Returning to the receiver 150, the data received by the receiver150 is then sent to an analyzer 152. The analyzer 152 may have a varietyof functions, similar to the processor circuit 109 of the on-skin sensorcontrol unit 44, including 1) modifying the signals from the sensor 42using calibration data and/or measurements from the temperature probe66, 2) determining a level of an analyte in the interstitial fluid, 3)determining a level of an analyte in the bloodstream based on the sensormeasurements in the interstitial fluid, 4) determining if the level,rate of change, and/or acceleration in the rate of change of the analyteexceeds or meets one or more threshold values, 5) activating an alarmsystem 156 and/or 94 if a threshold value is met or exceeded, 6)evaluating trends in the level of an analyte based on a series of sensorsignals, 7) determine a dose of a medication, and 7) reduce noise orerror contributions (e.g., through signal averaging or comparingreadings from multiple electrodes). The analyzer 152 may be simple andperform only one or a small number of these functions or the analyzer152 may perform all or most of these functions.

[0317] The output from the analyzer 152 is typically provided to adisplay 154. A variety of displays 154 may be used including cathode raytube displays (particularly for larger units), LED displays, or LCDdisplays. The display 154 may be monochromatic (e.g., black and white)or polychromatic (i.e., having a range of colors). The display 154 maycontain symbols or other indicators that are activated under certainconditions (e.g., a particular symbol may become visible on the displaywhen a condition, such as hyperglycemia, is indicated by signals fromthe sensor 42). The display 154 may also contain more complexstructures, such as LCD or LED alphanumeric structures, portions ofwhich can be activated to produce a letter, number, or symbol. Forexample, the display 154 may include region 164 to display numericallythe level of the analyte, as illustrated in FIG. 23. In one embodiment,the display 154 also provides a message to the patient to direct thepatient in an action. Such messages may include, for example, “EatSugar”, if the patient is hypoglycemic, or “Take Insulin”, if thepatient is hyperglycemic.

[0318] One example of a receiver/display unit 46, 48 is illustrated inFIG. 23. The display 154 of this particular receiver/display unit 46, 48includes a portion 164 which displays the level of the analyte, forexample, the blood glucose concentration, as determined by theprocessing circuit 109 and/or the analyzer 152 using signals from thesensor 42. The display also includes various indicators 166 which may beactivated under certain conditions. For example, the indicator 168 of aglucose monitoring device may be activated if the patient ishyperglycemic. Other indicators may be activated in the cases ofhypoglycemia (170), impending hyperglycemia (172), impendinghypoglycemia (174), a malfunction, an error condition, or when acalibration sample is needed (176). In some embodiments, color codedindicators may be used. Alternatively, the portion 164 which displaysthe blood glucose concentration may also include a composite indicator180 (see FIG. 24), portions of which may be appropriately activated toindicate any of the conditions described above.

[0319] The display 154 may also be capable of displaying a graph 178 ofthe analyte level over a period of time, as illustrated in FIG. 24.Examples of other graphs that may be useful include graphs of the rateof change or acceleration in the rate of change of the analyte levelover time. In some embodiments, the receiver/display unit is configuredso that the patient may choose the particular display (e.g., bloodglucose concentration or graph of concentration versus time) that thepatient wishes to view. The patient may choose the desired display modeby pushing a button or the like, for example, on an optional inputdevice 162.

[0320] The receiver/display units 46, 48 also typically include an alarmsystem 156. The options for configuration of the alarm system 156 aresimilar to those for the alarm system 104 of the on-skin sensor controlunit 44. For example, if glucose is the analyte, than the on-skin sensorcontrol unit 44 may include an alarm system 156 that warns the patientof conditions such as hypoglycemia, hyperglycemia, impendinghypoglycemia, and/or impending hyperglycemia. The alarm system 156 istriggered when the data from the analyzer 152 reaches or exceeds athreshold value. The threshold values may correspond to interstitialfluid glucose concentrations or sensor signals (e.g., current orconverted voltage values) which correlate to the above-mentioned bloodglucose levels.

[0321] The alarm system 156 may also, or alternatively, be activatedwhen the rate or acceleration of an increase or decrease in analytelevel reaches or exceeds a threshold value. For example, in the case ofa subcutaneous glucose monitor, the alarm system 156 might be activatedif the rate of change in glucose concentration exceeds a threshold valuewhich might indicate that a hyperglycemic or hypoglycemic condition islikely to occur.

[0322] The alarm system 156 may be configured to activate when a singledata point meets or exceeds a particular threshold value. Alternatively,the alarm may be activated only when a predetermined number ofdatapoints spanning a predetermined amount of time meet or exceed thethreshold value. As another alternative, the alarm may be activated onlywhen the datapoints spanning a predetermined amount of time have anaverage value which meets or exceeds the threshold value. Each conditionthat can trigger an alarm may have a different alarm activationcondition. In addition, the alarm activation condition may changedepending on current conditions (e.g., an indication of impendinghyperglycemia may alter the number of datapoints or the amount of timethat is tested to determine hyperglycemia).

[0323] The alarm system 156 may contain one or more individual alarms.Each of the alarms may be individually activated to indicate one or moreconditions of the analyte. The alarms may be, for example, auditory orvisual. Other sensory-stimulating alarm systems by be used includingalarm systems 156 that direct the on-skin sensor control unit 44 toheat, cool, vibrate, or produce a mild electrical shock. In someembodiments, the alarms are auditory with a different tone, note, orvolume indicating different conditions. For example, a high note mightindicate hyperglycemia and a low note might indicate hypoglycemia.Visual alarms may also use a difference in color or brightness toindicate different conditions. In some embodiments, an auditory alarmsystem might be configured so that the volume of the alarm increasesover time until the alarm is deactivated.

[0324] In some embodiments, the alarms may be automatically deactivatedafter a predetermined time period. In other embodiments, the alarms maybe configured to deactivate when the data no longer indicate that thecondition which triggered the alarm exists. In these embodiments, thealarms may be deactivated when a single data point indicates that thecondition no longer exists or, alternatively, the alarm may bedeactivated only after a predetermined number of datapoints or anaverage of datapoints obtained over a given period of time indicate thatthe condition no longer exists.

[0325] In yet other embodiments, the alarm may be deactivated manuallyby the patient or another person in addition to or as an alternative toautomatic deactivation. In these embodiments, a switch is provided whichwhen activated turns off the alarm. The switch may be operativelyengaged (or disengaged depending on the configuration of the switch) by,for example, pushing a button on the receiver/display unit 46, 48. Oneconfiguration of the alarm system 156 has automatic deactivation after aperiod of time for alarms that indicate an impending condition (e.g.,impending hypoglycemia or hyperglycemia) and manual deactivation ofalarms which indicate a current condition (e.g., hypoglycemia orhyperglycemia).

[0326] The receiver/display units 46, 48 may also include a number ofoptional items. One item is a data storage unit 158. The data storageunit 158 may be desirable to store data for use if the analyzer 152 isconfigured to determine trends in the analyte level. The data storageunit 158 may also be useful to store data that may be downloaded toanother receiver/display unit, such as a large display unit 48.Alternatively, the data may be downloaded to a computer or other datastorage device in a patient's home, at a doctor's office, etc. forevaluation of trends in analyte levels. A port (not shown) may beprovided on the receiver/display unit 46, 48 through which the storeddata may be transferred or the data may be transferred using an optionaltransmitter 160. The data storage unit 158 may also be activated tostore data when a directed by the patient via, for example, the optionalinput device 162. The data storage unit 158 may also be configured tostore data upon occurence of a particular event, such as a hyperglycemicor hypoglycemic episode, exercise, eating, etc. The storage unit 158 mayalso store event markers with the data of the particular event. Theseevent markers may be generated either automatically by thedisplay/receiver unit 46, 48 or through input by the patient.

[0327] The receiver/display unit 46, 48 may also include an optionaltransmitter 160 which can be used to transmit 1) calibrationinformation, 2) a signal to direct the transmitter 98 of the on-skinsensor control unit 44 to change transmission frequency or frequencybands, and/or 3) a signal to activate an alarm system 104 on the on-skinsensor control unit 44, all of which are described above. Thetransmitter 160 typically operates in a different frequency band thanthe transmitter 98 of the on-skin sensor control unit 44 to avoidcross-talk between the transmitters 98, 160. Methods may be used toreduce cross-talk and the reception of false signals, as described abovein connection with the transmitter 100 of the on-skin sensor controlunit 44. In some embodiments, the transmitter 160 is only used totransmit signals to the sensor control unit 44 and has a range of lessthan one foot, and preferably less than six inches. This then requiresthe patient or another person to hold the receiver/display unit 46 nearthe sensor control unit 44 during transmission of data, for example,during the transmission of calibration information. Transmissions mayalso be performed using methods other than rf transmission, includingoptical or wire transmission.

[0328] In addition, in some embodiments of the invention, thetransmitter 160 may be configured to transmit data to anotherreceiver/display unit 46, 48 or some other receiver. For example, asmall receiver/display unit 46 may transmit data to a largereceiver/display unit 48, as illustrated in FIG. 1. As another example,a receiver/display unit 46, 48 may transmit data to a computer in thepatient's home or at a doctor's office. Moreover, the transmitter 160 ora separate transmitter may direct a transmission to another unit or to atelephone or other communications device that alerts a doctor or otherindividual when an alarm is activated and/or if, after a predeterminedtime period, an activated alarm has not been deactivated, suggestingthat the patient may require assistance. In some embodiments, thereceiver/display unit is capable of one-way or two-way paging and/or iscoupled to a telephone line to send and/or receive messages fromanother, such as a health professional monitoring the patient.

[0329] Another optional component for the receiver/display unit 46, 48is an input device 162, such as a keypad or keyboard. The input device162 may allow numeric or alphanumeric input. The input device 162 mayalso include buttons, keys, or the like which initiate functions ofand/or provide input to the analyte monitoring device 40. Such functionsmay include initiating a data transfer, manually changing thetransmission frequency or frequency band of the transmitter 98,deactivating an alarm system 104, 156, inputting calibration data,and/or indicating events to activate storage of data representative ofthe event.

[0330] Another embodiment of the input device 162 is a touch screendisplay. The touch screen display may be incorporated into the display154 or may be a separate display. The touch screen display is activatedwhen the patient touches the screen at a position indicated by a “softbutton” which corresponds to a desired function. Touch screen displaysare well known.

[0331] In addition, the analyte monitoring device 40 may includepassword protection to prevent the unauthorized transmission of data toa terminal or the unauthorized changing of settings for the device 40. Apatient may be prompted by the display 154 to input the password usingthe input device 152 whenever a password-protected function isinitiated.

[0332] Another function that may be activated by the input device 162 isa deactivation mode. The deactivation mode may indicate that thereceiver/display unit 46, 48 should no longer display a portion or allof the data. In some embodiments, activation of the deactivation modemay even deactivate the alarm systems 104, 156. Preferably, the patientis prompted to confirm this particular action. During the deactivationmode, the processing circuit 109 and/or analyzer 152 may stop processingdata or they may continue to process data and not report it for displayand may optionally store the data for later retrieval.

[0333] Alternatively, a sleep mode may be entered if the input device162 has not been activated for a predetermined period of time. Thisperiod of time may be adjustable by the patient or another individual.In this sleep mode, the processing circuit 109 and/or analyzer 152typically continue to obtain measurements and process data, however, thedisplay is not activated. The sleep mode may be deactivated by actions,such as activating the input device 162. The current analyte reading orother desired information may then be displayed.

[0334] In one embodiment, a receiver/display unit 46 initiates anaudible or visual alarm when the unit 46 has not received a transmissionfrom the on-skin sensor control unit within a predetermined amount oftime. The alarm typically continues until the patient responds and/or atransmission is received. This can, for example, remind a patient if thereceiver/display unit 46 is inadvertently left behind.

[0335] In another embodiment, the receiver/display unit 46, 48 isintegrated with a calibration unit (not shown). For example, thereceiver/display unit 46, 48 may, for example, include a conventionalblood glucose monitor. Another useful calibration device utilizingelectrochemical detection of analyte concentration is described in U.S.patent application Ser. No. 08/795,767, incorporated herein byreference. Other devices may be used including those that operate using,for example, electrochemical and calorimetric blood glucose assays,assays of interstitial or dermal fluid, and/or non-invasive opticalassays. When a calibration of the implanted sensor is needed, thepatient uses the integrated in vitro monitor to generate a reading. Thereading may then, for example, automatically be sent by the transmitter160 of the receiver/display unit 46, 48 to calibrate the sensor 42.

[0336] Integration with a Drug Administration System

[0337]FIG. 25 illustrates a block diagram of a sensor-based drugdelivery system 250 according to the present invention. The system mayprovide a drug to counteract the high or low level of the analyte inresponse to the signals from one or more sensors 252. Alternatively, thesystem monitors the drug concentration to ensure that the drug remainswithin a desired therapeutic range. The drug delivery system includesone or more (and preferably two or more) subcutaneously implantedsensors 252, an on-skin sensor control unit 254, a receiver/display unit256, a data storage and controller module 258, and a drug administrationsystem 260. In some cases, the receiver/display unit 256, data storageand controller module 258, and drug administration system 260 may beintegrated in a single unit. The sensor-based drug delivery system 250uses data form the one or more sensors 252 to provide necessary inputfor a control algorithm/mechanism in the data storage and controllermodule 252 to adjust the administration of drugs. As an example, aglucose sensor could be used to control and adjust the administration ofinsulin.

[0338] In FIG. 25, sensor 252 produces signals correlated to the levelof the drug or analyte in the patient. The level of the analyte willdepend on the amount of drug delivered by the drug administrationsystem. A processor 262 in the on-skin sensor control unit 254, asillustrated in FIG. 25, or in the receiver/display unit 256 determinesthe level of the analyte, and possibly other information, such as therate or acceleration of the rate in the increase or decrease in analytelevel. This information is then transmitted to the data storage andcontroller module 252 using a transmitter 264 in the on-skin sensorcontrol unit 254, as illustrated in FIG. 25, or a non-integratedreceiver/display unit 256.

[0339] If the drug delivery system 250 has two or more sensors 252, thedata storage and controller module 258 may verify that the data from thetwo or more sensors 252 agrees within predetermined parameters beforeaccepting the data as valid. This data may then be processed by the datastorage and controller module 258, optionally with previously obtaineddata, to determine a drug administration protocol. The drugadministration protocol is then executed using the drug administrationsystem 260, which may be an internal or external infusion pump, syringeinjector, transdermal delivery system (e.g., a patch containing the drugplaced on the skin), or inhalation system. Alternatively, the drugstorage and controller module 258 may provide a the drug administrationprotocol so that the patient or another person may provide the drug tothe patient according to the profile.

[0340] In one embodiment of the invention, the data storage andcontroller module 258 is trainable. For example, the data storage andcontroller module 258 may store glucose readings over a predeterminedperiod of time, e.g., several weeks. When an episode of hypoglycemia orhyperglycemia is encountered, the relevant history leading to such eventmay be analyzed to determine any patterns which might improve thesystem's ability to predict future episodes. Subsequent data might becompared to the known patterns to predict hypoglycemia or hyperglycemiaand deliver the drug accordingly. In another embodiment, the analysis oftrends is performed by an external system or by the processing circuit109 in the on-skin sensor control unit 254 or the analyzer 152 in thereceiver/display unit 256 and the trends are incorporated in the datastorage and controller 258.

[0341] In one embodiment, the data storage and controller module 258,processing circuit 109, and/or analyzer 152 utilizes patient-specificdata from multiple episodes to predict a patient's response to futureepisodes. The multiple episodes used in the prediction are typicallyresponses to a same or similar external or internal stimulus. Examplesof stimuli include periods of hypoglycemia or hyperglycemia (orcorresponding conditions for analytes other than glucose), treatment ofa condition, drug delivery (e.g., insulin for glucose), food intake,exercise, fasting, change in body temperature, elevated or lowered bodytemperature (e.g., fever), and diseases, viruses, infections; and thelike. By analyzing multiple episodes, the data storage and controllermodule 258, processing circuit 109, and/or analyzer 152 can predict thecoarse of a future episode and provide, for example, a drugadministration protocol or administer a drug based on this analysis. Aninput device (not shown) may be used by the patient or another person toindicate when a particular episode is occurring so that, for example,the data storage and controller module 258, processing circuit 109,and/or analyzer 152 can tag the data as resulting from a particularepisode, for use in further analyses.

[0342] In addition, the drug delivery system 250 may be capable ofproviding on-going drug sensitivity feedback. For example, the data fromthe sensor 252 obtained during the administration of the drug by thedrug administration system 260 may provide data about the individualpatient's response to the drug which can then be used to modify thecurrent drug administration protocol accordingly, both immediately andin the future. An example of desirable data that can be extracted foreach patient includes the patient's characteristic time constant forresponse to drug administration (e.g., how rapidly the glucoseconcentration falls when a known bolus of insulin is administered).Another example is the patient's response to administration of variousamounts of a drug (e.g., a patient's drug sensitivity curve). The sameinformation may be stored by the drug storage and controller module andthen used to determine trends in the patient's drug response, which maybe used in developing subsequent drug administration protocols, therebypersonalizing the drug administration process for the needs of thepatient.

[0343] The present invention should not be considered limited to theparticular examples described above, but rather should be understood tocover all aspects of the invention as fairly set out in the attachedclaims. Various modifications, equivalent processes, as well as numerousstructures to which the present invention may be applicable will bereadily apparent to those of skill in the art to which the presentinvention is directed upon review of the instant specification. Theclaims are intended to cover such modifications and devices.

What is claimed is:
 1. An insertion kit for inserting an electrochemicalsensor into a patient, the insertion kit comprising: an insertercomprising a portion having a sharp, rigid, planer structure adapted tosupport the sensor during insertion of the electrochemical sensor; andan insertion gun having a port configured to accept the electrochemicalsensor and the inserter, a driving mechanism for driving the inserterand the electrochemical sensor into the patient, and a retractionmechanism for removing the inserter from the patient while leaving thesensor within the patient.
 2. The insertion kit of claim 1, wherein theinsertion gun further comprises a cocking mechanism to maintain theinserter and electrochemical sensor in a cocked position prior toinsertion into the patient, and a release mechanism to release theinserter and electrochemical sensor from the cocked position and permitthe driving mechanism to drive the inserter and electrochemical sensorinto the patient.
 3. The insertion kit of claim 1, further comprising anelectrochemical sensor for insertion into the patient using the inserterand insertion gun.
 4. The insertion kit of claim 3 wherein theelectrochemical sensor includes a barb to facilitate retention of thesensor within the patient.
 5. The insertion kit of claim 3 wherein theelectrochemical sensor is flexible.
 6. The insertion kit of claim 1,wherein the insertion gun and inserter are configured to insert theelectrochemical sensor into the patient at a depth of between about 2 to12 mm.
 7. The insertion kit of claim 1, wherein the insertion gun andinserter are configured to insert the electrochemical sensor into thepatient at an angle between about 15° to 60° relative to a surface ofthe patient.
 8. The insertion kit of claim 1, wherein the inserter has across-sectional width of 1 mm or less.
 9. The insertion kit of claim 1,wherein the inserter has a cross-sectional height of 1 mm or less. 10.The insertion kit of claim 1, wherein the inserter gun is configured tomate with a mounting base of a sensor control unit.